Method for the prophylaxis and/or treatment of medical disorders

ABSTRACT

The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Application Ser. No. 60/140,345, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to a method for the prophylaxis and/or treatment of medical disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on cells such as epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a particularly preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis or neovascularization conditions such as neovascularization of the retina. The present invention is further directed to the subject genetic molecules in adjunctive therapy for epidermal hyperplasia, such as in combination with UV treatment, and to facilitate apoptosis of cancer cells and in particular cancer cells comprising keratinocytes.

BACKGROUND OF THE INVENTION

Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia or any other country.

Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population. The condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis.

One important group of growth factors are the dermally-derived insulin-like growth factors (IGFs) which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as “progression factors” promoting “competent” cells through DNA synthesis. The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues [1].

Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability [2]. Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed [3]. There is some evidence, however, that certain IGFBPs are involved in targeting IGF-I to its cell surface receptor.

Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fibroblasts [4]. Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6 [5] which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I [6].

It is apparent, therefore, that IGF-I and other growth promoting molecules, are responsible for or at least participate in a range of skin cell activities. In accordance with the present invention, the inventors have established that aberrations in the normal functioning of these molecules or aberrations in their interaction with their receptors is an important factor in a variety of medical disorders such as proliferative and/or inflammatory skin disorders. It is proposed, therefore, to target these molecules or other molecules which facilitate their functioning or interaction with their receptors to thereby ameliorate the effects of aberrant activity during or leading to skin disease conditions and other medical conditions such as those involving neovascularization. Furthermore, these molecules may also be used to facilitate apoptosis of target cells and may be useful as adjunctive therapy for epidermal hyperplasia.

SUMMARY OF THE INVENTION

Nucleotide and amino acid sequences are referred to by a sequence identifier, i.e. (<400>1), (<400>2), etc. A sequence listing is provided after the claims.

Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.

According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.

According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to <400>1 or <400>2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.

Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3. In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.

Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents.

Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor.

Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder.

The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representation of the nucleotide sequence of IGFBP-2. LOCUS HSIGFBP2 1433 bp RNA PRI 31-JAN-1990 5 DEFINITION Human mRNA for insulin-like growth factor binding protein (IGFBP-2) ACCESSION X16302 KEYWORDS insulin-like growth factor binding protein. SOURCE human ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia;

Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae. REFERENCE 1 (bases 1 to 1433) AUTHORS Binkert,C., Landwehr,J., Mary,J.L., Schwander,J. and Heinrich,G. TITLE Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2) JOURNAL EMBO J. 8, 2497-2502 (1989) STANDARD full automatic COMMENT NCBI gi: 33009 FEATURES Location/Qualifiers source 1. .1433 /organism=“Homo sapiens” /dev_stage=“fetal” /tissue_type=“liver” misc_feature 1416. .1420 /note=“pot. polyadenylation signal” polyA site 1433 /note=“polyadenylation site” CDS 118. .1104 /note=“precursor polypeptide; (AA −39 to 289); NCBI gi:33010.” /codon start=1 /translation=“MLPRVGCPALPLPPPPLLPLLPL LLLLLGASGGGGGARAEVLFRCPPCTPERLAACGPPP VAPPAAVAAVAGGARNPCAELVREPGCGCCSVCARLE GEACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTC EKRRDAEYGASPEQVADNGDDHSEGGLVENHVDSTMN TMNMLGGGGSAGRKPLKSGMKELAVFREKVTEQHRQM GKGGKNHLGLEEPKKLRPPPARTPCQQELDQVLERIS TMRLPDERGPLEHLYSLHIPNCDKHGLYNLKQCKMSL NGORGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQ QEACGVHTQRMQ” (<400>21) CDS 118. .234 /note=“signal peptide; (AA −39 to −1); NCBI gi: 33011.” /codon_start=1 /translation=“MLPRVGCPALPLPPPPLLPLLPL LLLLLGASGGGGGARA” (<400>22) CDS 235. .1101 /note=“mature IGFBP-2; (AA 1 to 289); NCBI gi: 33012.” /codon_start=1 /translation=“EVLFRCPPCTPERLAACGPPPVA PPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGE ACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEK RRDAEYGASPEQVADNGDDHSEGGLVENHVDSTMNML GGGGSAGRKPLKSGMKELAVFREKVTEQHRQMGKGGI GKHHLGLEEPKKLRPPPARTPCQQELDQVLERISTMR LPDERGPLEHLYSLHIPNCDKHGLYNLKQCKNSLNGQ RGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEA CGVHTQRMQ” (<400>23) BASE COUNT 239 a  466 c  501 g  227 t ORIGIN HSIGFBP2 Length: 1433 May 11, 1994 10:06 Type: N Check: 6232 . .

FIG. 2 is a representation of the nucleotide sequence of IGFBP-3. LOCUS HUMGFIBPA 2474 bp ss-mRNA PRI 15-JUN-1990 DEFINITION Human growth hormone-dependent insulin-like growth factor-binding protein mRNA, complete cds. ACCESSION M31159 KEYWORDS insulin-like growth factor binding protein. SOURCE Human plasma, cDNA to mRNA, clone BP-53. ORGANISM Homo sapiens Eukaryota; Animalia; Chordata; Vertebrata; Mammalia; Theria;

Eutheria; Primates; Haplorhini; Catarrhini; Hominidae. REFERENCE 1 (bases 1 to 2474) AUTHORS Wood,W.I., Cachianes,G., Henzel,W.J., Winslow,G.A., Spencer,S.A., Hellmiss,R., Martin,J.L. and Baxter,R.C.

TITLE Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein JOURNAL Mol. Endocrinol. 2, 1176-1185 (1988) STANDARD full automatic 30 COMMENT NCBI gi: 183115 FEATURES Location/Qualifiers mRNA <1. .2474 /note=“GFIBP mRNA” CDS 110. .985 /gene=“IGFBP1” /note=“insulin-like growth factor- binding protein; NCBI gi: 183116.” /codon_start=1 /translation=“MQRARPTLWAAALTLLVLLRGPP VARAGASSGGLGPVVRCEPCDARALAQCAPPPAVCAE LVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPS PDEARPLQALLDGRGLCVNASAVSRLRAYLLPAPPAP GNASESEEDRSAGSVESPSVSSTHRVSDPKFHPLHSK IIIIKKGHAXDSQRYKVDYESQSTDTQNFSSESKRET EYGPCRREMEDTLNHLKFLNVLSPRGVHIPNCDKKGF YKKKQCRPSKGRKRGFCWCVDKYGQPLPGYTTKGKED VHCYSMQSK” (<400>24>) source 1. .2474 /organism=“Homo sapiens” BASECOUNT 597 a  646 c  651 g  580 t ORIGIN misc_feature 1343. .1351 /note=“pot.N-linked glycosylation site (AA 408-410)” misc_feature 1631. .1639 /note=“pot.N-linked glycostlation site (AA 504-506)” misc_feature 1850. .1858 /note=“pot.N-linked glycosylation site (AA 577-579)” misc_feature 1895. .1903 /note=“pot.N-linked glycosylation site (AA 592-594)” misc_feature 1949. .1957 /note=“pot.N-linked glycosylation site (AA 610-612)” misc_feature 2240. .2251 /note=“putative proreceptor processing site (AA 707-710) misc_feature 2252. .4132 /note=“beta-subunit (AA 711-1337)” misc_feature 2270. .2278 /note=“pot.N-linked glycosylation site (AA 717-719]” misc_feature 2297. .2305 /note=“pot.N-linked glycosylation site (AA 726-728)” misc_feature 2321. .2329 /note=“pot.N-linked glycosylation site (AA 734-736)” misc_feature 2729. .2737 /note=“pot.N-linked glycosylation site (AA 870-872)” misc_feature 2768. .2776 /note=“pot.N-linked glycosylation site (AA 883-885)” misc_feature 2837. .2908 /note=“transmembrane region (AA 906-929)” misc_feature 2918. .2926 /note=“pot.N-linked glycosylation site (AA 933-935)” misc_feature 3047. .3049 /note=“pot.ATP binding site (AA 976)” misc_feature 3053. .3055 /note=“pot.ATP binding site (AA 978)” misc_feature 3062. .3064 /note=“pot.ATP binding site (AA 981)” misc_feature 3128. .3130 /note=“pot.ATP binding site (AA 1003)” CDS 32. .4132 /product=“IGF-I receptor” /note=“50 stops when translation attempted, frame 1, code 0” BASE COUNT 1216 a  1371 c  1320 g  1082 t ORIGIN HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N Check: 133 . .

FIG. 4A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 and BP3S) at 0.5 μM and 5 μM; * no oligonucleotide added.

FIG. 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (FIG. 4A), showing relative band intensities of IGFBP-3 and the 24 kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides; * no oligonucleotide added.

FIG. 5A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5 μM compared with several control oligonucleotides at 0.5 μM. (a) oligonucleotide BP3AS2NS; (b) oligonucleotide BP3AS4; (c) oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.

FIG. 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (FIG. 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in FIG. 5A, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide.

FIG. 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense; IGFR.S: sense.

FIG. 7 is a graphical representation showing inhibition of IGFBP-3 production in culture medium following initial treatment with antisense oligonucleotides once daily over a 2 day period.

FIG. 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.

FIG. 9 is a diagramatic representation of a map of IGF-1 Receptor mRNA and position of target ODNs.

FIG. 10 is a photographical representation showing Lipid-mediated uptake of oligonucleotide in keratinocytes. HaCaT keratinocytes were incubated for 24 hours in medium 10 (DMEM plus 10% v/v FCS) containing fluorescently labelled ODN (R451, 30 nM) and cytofectin GSV (2 μg/ml). The cells were then transferred to ODN-free medium and fluorescence microscopy (a) and phase contrast (b) images of the cells were obtained.

FIG. 11 is a graphical representation of uptake (A) and toxicity (B) of ODN/lipid complexes in keratinocytes. Confluence HaCaT keratinocytes were incubated in DMEM containing fluoresently labelled ODN (R451) plus liposome over 120 hours, viewed using fluorescene microscopy and trypan blue stained and counted.

FIG. 12 is a graphical representation of an IGF-1 Receptor mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml GSV). HaCaT keratinocytes were treated for 96 hours with C-5 propynyl, dU, dC ODNs complexed with cytofectin GSV. Cells were treated with ODNs complementary to the human IGF-I receptor mRNA (27, 32, 74 and 78), 2 randomised sequence ODNs (R451) and R766), liposome alone (GSV) or were left untreated (UT). Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase Protection and Phosphorlmager quantitiation.

(A) Electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase Protection. Molecular weight markers are shown on the right hand side. Full length probe is shown on the left hand side (G-probe and I-probe). GAPDH protected fragments (G) are seen at 316 bases and IGF-I receptor protected fragments (1) are seen at 276 bases.

(B) Relative level of IGF-I receptor mRNA following each treatment is shown.

FIG. 13 is a graphical representation of an IGF-1 receptor mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml GSV). Summary of IGF-I receptor ODN screening data. HaCaT keratinocytes were treated for 96 hours with C-5 propynyl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase protection and phosphorImager quantitiation. Relative level of IGF-I receptor mRNA is shown after treatment with ODNs complementary to the human IGF-I receptor mRNA, 4 randomised sequence ODNs and liposome alone. (26-86=IGF-I receptor ODNs; R1, R4, R7 and R9=randomised ODNs (R1=R121, R4=R451, R7=R766, R9=R961); GSV=liposome alone; UT=untreated). *indicates a significant difference in relative IGF-I receptor mRNA from GSV treated cells (n=4-10, p<0.05).

FIG. 14 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes. HaCaT cells were grown to confluence in 24-well plates in DMEM containing 10% v/v FCS. Oligodeoxynucleotide (ODN) and Cytofectin GSV (GSV, Glen Research) were mixed together in serum-free DMEM, incubated at room temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells. Cells were incubated for 72 hours with 30 nM random sequence or antisense ODN and 2 μg/ml GSV or with GSV alone in DMEM containing 10% v/v FCS with solutions replaced every 24 hours. This was followed by incubation with ODN/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37° C. Wells were washed twice with 1 ml cold PBS. Serum-free DMEM containing 10⁻¹⁰M ¹²⁵I-IGF-I was added with or without the IGF-I analogue, des (1-3) IGF-I, at 10⁻¹⁰M to 10⁻⁷M. Cells were incubated at 4° C. for 17 hours with gentle shaking then washed three times with 1 ml cold PBS and lysed in 250 μl 0.5M NaOH/0.1% v/v Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a γ counter.

FIG. 15 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes.

FIG. 16 is a photographical representation of H & E stained sections of (A) psoriatic skin biopsy prior to grafting and (B) 49 day old psoriatic skin graft using skin from the same donor.

FIG. 17 is a photographical representation of uptake of oligonucleotide after intradermal injection into psoriatic skin graft on a nude mouse. Psoriatic skin graft was intradermally injected with ODN (R451, 50 μl, 10 μM). The graft was removed and sectioned after 24 hours, then viewed using confocal microscopy.

FIG. 18(a) is a photographical representation of Pregraft, Donor JH, Donor JH, PBS treated, 50 μl, Donor JH, #50 treated, 50 μl, 10 μM.

FIG. 18(b) is a photographical representation of Donor LB, pregraft, Donor LB, PBS treated (50 μl), Donor LB, #74 treated (50 μl, 10 μM).

FIG. 18(c) is a photographical representation of Donor PW, pregraft, Donor PW, R451 treated (50 μl, 10 μM), Donor LB, #74 treated (50 μl, 10 μM).

FIG. 18(d) is a photographical representation of Donor GM, pregraft, Donor GB, R451 treated (50 μl, 10 μM), Donor GM, #27 treated (50 μl, 10 μM).

FIG. 19(a) is a photographical representation showing Donor JH pregraft, Donor JH PBS treated 50, μl, Donor JH #50 treated 50 μl, 10 μM.

FIG. 19(b) is a photographical representation Donor LB pregraft, Donor LB PBS treated 50 μl, Donor LB #74 treated 50 μl, 10 μM.

FIG. 19(c) is a photographical representational showing Donor PW pregraft, Donor PW R451 treated 50 μl, 10 μM, Donor PW #74 treated 50 μl, 10 μM.

FIG. 19(d) is a photographical representation showing Donor GM pregraft, Donor GM R451 treated 50, μl, 10 μM, Donor #27 treated 50, μl, 10 μM.

FIG. 20 is a graphical representation showing suppression of psoriasis after treatment with oligonucleotide (quantification). Oligonucleotide (50 μl, 10 μM) was injected every two days for 20 days, as were control treatments. Skin thickness was measured by removing the skin and using computer software (MCID analysis) to measure the exact thickness of each graft. N=3-4 for each treatment. *indicates a significant difference from the pregraft value (ANOVA, P<0.05)

FIG. 21 is a photographic representation of αhKi-67 imunobiological binding.

FIG. 22 is a photographical representation showing penetration of oligonucleotide into human skin after topical treatment. Fluorescently labelled oligonucleotide (10 μM R451) was applied topically after formulation with cytofectin GSV (10 μg/ml) and viewed using confocal microscopy.

FIG. 23 is a photographical representation showing penetration of oligonucleotide into human skin after application of topical gel formation. Fluorescently labelled oligonucleotide (10 μM R451) was applied topically after complexing with cytofectin GSV (10 μg/ml) and formulation into 3% methylcellulose gel. Image was obtained using confocal microscopy.

FIG. 24 is a graphical representation showing IGFBP-3 mRNA.

FIG. 25(a) is a graphical representation showing IGFBP-3 mRNA in AON treated (10 nM) HaCaT cells (2 μg/ml GSV).

FIG. 25(b) is a graphical representation showing IGFBP-3 mRNA levels of AON treated (100 nm) HaCaT cells (2 μg/ml GSV).

FIG. 25(c) is a graphical representation showing IGFBP-3 mRNA in AON treated (30 nM) HaCaT cells (2 μg/ml GSV).

FIG. 25(d) is a graphical representation showing IGFBP-3 mRNA in AON treated (30 nM) HaCaT cells (2 μg/ml GSV).

FIG. 26(a) is a graphical representation showing IGFBP-3 mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml). HaCaT keratinocytes were treated for 51 hours with C-5 propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP-3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation. Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and lipsome alone. (1-24=IGFBP-3 ODNs; R1, R4, R7 and R9=randomised ODNs (R1=R121, R4=R451, R7=R766, R9 R961); GS=liposome alone; UT=untreated). *indicates a significant different in relative IGFBP-3 mRNA from GSV treated cells (n-5-8, p<0.01), **indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells (n=5-8, p<0.05).

FIG. 26(b) is a graphical representation showing IGFBP-3 mRNA in ODN treated (100 nM) HaCaT cells (2 μg/ml GSV). HaCaT keratinocytes were treated for 51 hours with C-5 propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP-3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation. Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and liposome alone. (1-24=IGFBP-3 ODNs; R1, R4, R7 and R9=randomised ODNs (R1-R121, R4=R451, R7=R766, R9-R961), GS=lipsome alone; UT=untreated). *indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells (n-6-8, p<0.01).

FIG. 27 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT cells following treatment with antisense oligonucleotides. Confluent HaCaT cells were treated every 24 h for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA by RNase protection assay. (a). Representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. In this example, a reduction in IGFR band intensity relative to GAPDH can be seen with AON #27 and #78, but not with #32, #74 or the controls (R4, R7, random oligonucleotides R451 and R766, respectively; G, GSV lipid; UT, untreated).

(b) Densitometric quantitation of IGF-I receptor mRNA (normalised to GAPDH mRNA) in HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black), random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar). Each oligonucleotide was assayed in duplicate in at least two separate experiments.

Results are presented as mean±SEM. A one-way ANOVA followed by Tukey's (▴) test was performed; ▴ indicates a significant difference between cells treated with IGF-I receptor specific AONs and all of the control treatments (p<0.05). n=4 except for #27 and #32 (n=6), #28 and #68 (n=3), R766 (n=9), and R451, GSV and untreated (n=10).

FIG. 28 is a representation showing a reduction in total cellular IGF-I receptor protein following antisense oligonucleotide treatment. Confluent HaCaT cells were treated every 24 h for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONs (#27, #50 and #64) or the random sequence oligonucleotide, R451. Total cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with an antibody specific for the human IGF-I receptor. (a) Duplicate treated cellular extracts showing the IGF-I receptor at the predicted size of 110 kD

(b) Densitometric quantitation of IGF-I receptor protein. Results are presented as mean±SEM of four different experiments each performed in duplicate. A one-way ANOVA followed by a Dunnett's test was performed; * indicates a significant difference from GSV treated cells (p<0.01). GSV, GSV lipid alone; UT, untreated; R451, random sequence oligonucleotide; 64, 50, 27, IGF-I receptor-specific AONs.

FIG. 29 is a representation showing a reduction in IGF-I receptor numbers on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were transfected with IGF-I receptor specific AONs #27 (-▴-), #50 (-x-), #64 (---▪---), a random sequence oligonucleotide R451 (-o-), or treated with GSV lipid alone (--□--) every 24 h for four days (untreated cells, --*--). Competition binding assays using ¹²⁵I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I, were performed (inset); plotted values are means ±standard error. The mean values were then subjected to Scatchard analysis.

FIG. 30 is a representation showing a reduction in keratinocyte cell number following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6416, or treated with GSV lipid alone every 24 h for 2 days (UT, untreated cells). Cell number was measured in the culture wells using a dye binding assay (Experimental protocol). Results are presented as mean±SD. A one-way ANOVA was performed, followed by a Tukey's multiple comparison test. ▴ indicates a significant difference between cells treated with AON #64 and all of the control treatments (p<0.001).

FIG. 31 is a representation showing a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides

Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed histologically. (a) Donor A graft treated with AON #50 showing epidermal thinning compared

with pregraft and control (PBS) treated graft, and Donor B graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. E, epidermis; Scale bar, 400 mm; all pictures are at the same magnification. (b) Mean epidermal cross-sectional area over the full width of grafts was determined by digital image analysis. Results are presented as mean±SEM. Shaded bars, control treatments: R451, random oligonucleotide sequence; solid bars, treatments with oligonucleotides that inhibited IGF-I receptor expression in vitro. * indicates a significant difference from the vehicle treated graft (p<0.01, n=5-7), ++ indicates a significant difference from the random sequence (R451) treated graft (p<0.01, n=5-7). (c) Parakeratosis (arrow) was absent in grafts treated with IGF-I receptor AONs (AON #50) but persisted in pregraft and control (PBS) treated graft. Scale bar, 100 mm.

FIG. 32 is a representation showing a reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides (a) A psoriasis lesion prior to grafting, and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) was immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). Scale bar, 250 mm; all pictures are at the same magnification. (b) The same lesion prior to grafting and after oligonucleotide treatment as in (a) was subjected to in situ hybridisation with a ³⁵S-labeled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains (tiny black speckles), which are almost eliminated in the epidermis of the lesion treated with the IGF-I receptor-specific oligonucleotide #27 (AON #27). Arrows indicate the basal layer of the epidermis with dermis underneath. Scale bar, 50 μm.

FIG. 33 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to 90% confluence in DMEM contianing 10% v/v fetal calf serum were treated with 24 h for two days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially availble ribonuclease protection assay kit (RPAII, Ambicon Inc, Austin, Tex.). Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, Calif.).

FIG. 34 is a representation showing a reduction in IGF-I receptor protein in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to 90% confluence in DMEM containing 10% v/v fetal calf serum were treated every 24 h for four days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Cells were lyased in a buffer containing 50 mM HEPES, 150 mM NaCl, 10% v/v gycerol, 1% v/v Triton X-100 and 100 μg/ml aprotinin on ice for 30 mins, then 30 μg of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane (Millipore, Bedford, Mass.). Membranes were incubated with the anti-IGF-I receptor antibody C20 (Sanra Cruz Biotechnology Inc., Santa Cruz, Calif., 25 ng/ml in 150 mM NaCl, 10 mM Tris-HCl, pH 7.4, 0.1% v/v Tween 20) for 1 h at room temperature and developed using the Vistra ECF western blotting kit (Amersham, Buckinghamshire, England). Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, Calif.).

FIG. 35 is a representation showing a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. HaCaT cell monolayers grown to 40% confluence in DMEM containing 10% fetal calf serum were treated every 24 h for three days with 2 μg/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell number was measured every 24 h using the amido black dye binding assay [32].

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is predicated in part on the use of molecules and in particular genetic molecules and more particularly antisense molecules to down-regulate a growth factor, its receptor and/or growth factor expression facilitating sequences.

Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.

Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and these and other medical disorders may be mediated by any number of molecules such as but not limited to IGF-I, keratinocyte growth factor (KGF), transforming growth factor-α (TGFα), tumour necrosis factor-α (TNFα), interleukin-1, -4, -6 and 8 (IL-1, IL-4, IL-6 and IL-8, respectively), basic fibroblast growth factor (bFGF) or a combination of one or more of the above. The present invention is particularly described and exemplified with reference to IGF-I and its receptor (IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, since targeting these molecules according to the methods contemplated herein provides the best results to date. This is done, however, with the understanding that the present invention extends to any growth factor or cytokine-like molecule, a receptor thereof or a facilitating molecule like the IGFBPs involved in skin cell proliferation such as those molecules contemplated above and/or their receptors and/or facilitating molecules therefor.

According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.

The present invention is particularly described by psoriasis as the proliferative skin disorder. However, the subject invention extends to a range of proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of the skin. The present invention extends to a range of other disorders such as neovascularization conditions such as but not limited to hyperneovasularization such as neovascularization of the retina, lining of the brain, skin, hyperproliferation of the inside of blood vessels, kidney disease, atherosclerotic disease, hyperplasias of the gut epithelium or growth factor mediated malignancies such as IGF1-mediated malignancies.

Furthermore, down-regulation of IGF-I receptor is useful as adjunctive therapy for epidermal hyperplasia. In accordance with this aspect of the present invention it is known that IGF-I receptor elicits separate intracellular signals which prevent apoptosis [19]. In keratinocytes, IGF-I receptor activation has been shown to protect UV-irradiated cells from apoptosis [20]. In another cell type, a number of IGF-I receptors expressed by the cells correlated with tumorigenicity and apoptotic resistance [21]. Consequently, in accordance with the present invention, by inactivating IGF-I receptor on cells such as epidermal keratinocytes will achieve three important outcomes:

-   -   (i) Acute epidermal hyperplasia following UV has been suggested         to increase the risk of keratinocyte carcinogenic transformation         [22]. By reducing IGF-I receptor expression in the epidermis,         the incidence of epidermal hyperplasia following UV exposure is         likely to be reduced leading to an overall acceleration in         normalization of the lesion and reduced carcinogenic risk.     -   (ii) Inhibition of anti-apoptotic action of IGF-I receptor will         enhance the reversal of epidermal thickening and accelerate         normalization of differentiation. Topical or injected IGF-I         receptor antisense as adjunctive treatment will increase         apoptosis in the epidermal layer thereby enhancing the reduction         in acanthosis observed in UV treatments.     -   (iii) Survival of keratinocytes, ie. those which evade apoptosis         is likely to occur when cells have damaged DNA. Such mutations         may be in the tumor suppressor region. Consequently, the use of         antisense therapy will result in less frequent selection of         mutated keratinocytes and therefore reduced incidence of basal         cell carcinomas and squamous.

According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

The UV treatment and nucleic acid molecule or its chemical analogue may be administered in any order or may be done simultaneously. This method is particularly useful in treating psoriasis by combination of UV and antisense therapy. Preferably the antisense therapy is directed to the IGF-I receptor.

In a preferred embodiment, the present invention is directed to a method for ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder.

The present invention extends to any mammal such as but not limited to humans, livestock animals (e.g. horses, sheep, cows, goats, pigs, donkeys), laboratory test animals (e.g. rabbits, mice, guinea pigs), companion animals (e.g. cats, dogs) and captive wild animals. However, the instant invention is particularly directed to proliferative and/or inflammatory skin disorders such as psoriasis in humans as well as medical disorders contemplated above.

The aspects of the subject invention instantly contemplated are particularly directed to the topical application of one or more suitable nucleic molecules capable of inhibiting, reducing or otherwise interfering with IGF-mediated cell proliferation and/or inflammation. More particularly, the nucleic acid molecule targets IGF-I interaction with its receptor. Conveniently, therefore, the nucleic acid molecule is an antagonist of IGF-I interaction with its receptor. Most conveniently, the nucleic acid molecule antagonist is an antisense molecule to the IGF-I receptor, to IGF-I itself or to a molecule capable of facilitating IGF-I interaction with its receptor such as but not limited to an IGFBP.

Insofar as the invention relates to IGFBPs, the preferred molecules are IGFBP-2, -3, -4, -5 and -6. The most preferred molecules are IGFBP-2 and IGFBP-3.

The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in FIGS. 1 (<400>1) and 2 (<400 >2), respectively. According to a particularly preferred aspect of the present invention, there is provided a nucleic acid molecule comprising at least about ten nucleotides capable of hybridising to, forming a heteroduplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to a genomic form of <400>1 and/or <400>2 and which thereby reduces or inhibits translation of said mRNA molecule. Preferably, the nucleic acid molecule is at least about 15 nucleotides in length and more preferably at least about 20-25 nucleotides in length. However, the instant invention extends to any length nucleic acid molecule including a molecule of 100-200 nucleotides in length to correspond to the full length of or near full length of the subject genes.

The nucleotide sequence of the antisense molecules may correspond exactly to a region or portion of <400>1 or <400>2 or may differ by one or more nucleotide substitutions, deletions and/or additions. It is a requirement, however, that the nucleic acid molecule interact with an mRNA molecule to thereby reduce its translation into active protein.

Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 are those capable of interacting with sequences selected from the lists in Examples 6 and 7, respectively.

The nucleic acid molecules in the form of an antisense molecule may be linear or covalently closed circular and single stranded or partially double stranded. A double stranded molecule may form a triplex with target mRNA or a target gene. The molecule may also be protected from, for example, nucleases, by any number of means such as using a nonionic backbone or a phosphorothioate linkage. A convenient nonionic backbone contemplated herein is ethylphosphotriester linkage or a 2′-O-methylribosyl derivative. A particularly useful modification modifies the DNA backbone by introducing phosphorothioate internucleotide linkages. Alternatively or in addition to the pyrimidine bases are modified by inclusion of a C-5 propyne substitution which modification is proposed to enhance duplex stability [23]. The present invention extends to any chemical modification to the bases and/or RNA or DNA backbone. Reference to a “chemical analogue” of a nucleic acid molecule includes reference to a modified base, nucleotide, nucleoside or phosphate backbone.

Examples of suitable oligonucleotide analogues are conveniently described in Ts'O et al [7]. Further suitable examples of oligonucleotide analogues and chemical modifications are described in references 25 to 31.

Alternatively, the antisense molecules of the present invention may target the IGF-I gene itself or its receptor or a multivalent antisense molecule may be constructed or separate molecules administered which target at least two or an IGFBP, IGF-I and/or IGF-I-receptor. Examples of suitable antisense molecules capable of targetting the IGF-I receptor are those capable of interacting with sequences selected from the list in Example 8. One particularly useful antisense molecule is 5′-ATCTCTCCGCTTCCTTTC-3′ (<400>10).

Other particularly useful antisense molecules are: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG #78 UCUCCGCUUCCUUUC #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC #40 UAACAGAGGUCAGCA #42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG #50 GGCAGGCAGGCACAC

Particularly useful molecules are selected from #27, #64 and #78. In a preferred embodiment these molecules comprise a C-5 propynyl dU, dC phosphorothioate modification.

A particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said medical disorder with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3.

Preferably, the nucleic acid molecule are antisense molecules. Particularly useful antisense molecules are: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG #78 UCUCCGCUUCCUUUC #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC #40 UAACAGAGGUCAGCA #42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG #50 GGCAGGCAGGCACAC

Even more particularly useful molecules are selected from #27, #64 and #78.

In accordance with one aspect of the present invention the nucleic acid molecule is topically applied in aqueous solution or in conjunction with a cream, ointment, oil or other suitable carrier and/or diluent. A single application may be sufficient depending on the severity or exigencies of the condition although more commonly, multiple applications are required ranging from hourly, multi-hourly, daily, multi-daily, weekly or monthly, or in some other suitable time interval. The treatment might comprise solely the application of the nucleic acid molecule or this may be applied in conjunction with other treatments for the skin proliferation and/or inflammatory disorder being treated or for other associated conditions including microbial infection, bleeding and the formation of a variety of rashes.

As an alternative to or in conjunction with antisense therapy, the subject invention extends to the nucleic acid molecule as, or incorporating, a ribozyme including a minizyme to, for example, IGF-I, its receptor or to molecules such as IGFBPs and in particular IGFBP-2 and -3. Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach [8] and in International Patent Application No. WO 89/05852. The present invention extends to ribozymes which target mRNA specified by genes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2 and/or IGFBP-3.

According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to (<400>1) or (<400>2) wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.

Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3. In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.

The efficacy of the nucleic acid molecules of the present invention can be conveniently tested and screened using an in vitro system comprising a basal keratinocyte cell line. A particularly useful system comprises the HaCaT cell line described by Boukamp et al [9]. In one assay, IGF-I is added to an oligonucleotide treated HaCaT cell line. Alternatively, growth of oligonucleotide treated HaCaT cells is observed on a feeder layer of irradiated 3T3 fibroblasts. Using such in vitro assays, it is observed that antisense oligonucleotides to IGFBP-3, for example, inhibit production of IGFBP-3 by HaCaT cells. Other suitable animal models include the nude mouse/human skin graft model (15; 16) and the “flaky skin” mouse model (17; 18). In the nude mouse model, microdermatome biopsies of psoriasis lesions are taken under local anaesthetic from volunteers then transplanted to congenital athymic (nude) mice. These transplanted human skin grafts maintain the characteristic hyperproliferating epidermis for 6-8 weeks. They are an established model for testing the efficacy of topically applied therapies for psoriasis. In the “flaky skin” mouse model, the fsn/fsn mutation produces mice with skin resembling human psoriasis. This mouse, or another mutant mouse with a similar phenotype is a further in vivo model to test the efficacy of topically applied therapies for psoriasis.

Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents. Preferably, the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for co-suppression of one or more of these targets. The composition may comprise a single species of a nucleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.

The nucleic acid molecules may be administered in dispersions prepared in creams, ointments, oil or other suitable carrier and/or diluent such as glycerol, liquid polyethylene glycols and/or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersions. In all cases, the form is preferably sterile although this is not an absolute requirement and is stable under the conditions of manufacture and storage. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants. The prevention of the action of microorganism can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

Topical solutions are prepared by incorporating the nucleic acid molecule compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by where necessary filter sterilization.

The active agent may alternatively be administered by intravenous, subcutaneous, nasal drip, suppository, implant means amongst other suitable routes of administration including intraperitoneal, intramuscular, absorption through epithelial or mucocutaneous linings for example via nasal, oral, vaginal, rectal or gastrointestinal administration. Reference may conveniently be made to reference 24.

As used herein “pharmaceutically acceptable carriers and/or diluents” include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Conveniently, the nucleic acid molecules of the present invention are stored in freeze-dried form and are reconstituted prior to use.

Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor. The proliferative and/or inflammatory skin disorder is generally psoriasis or other medical disorders as described above and the nucleic acid molecule targets IGF-I, the IGF-I receptor and/or an IGFBP such as IGFBP-2 and/or IGFBP-3.

Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder.

The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor. Such a use is appropriate for the treatment of certain cancers and as adjunct therapy for epidermal hyperplasia such as in combination with UV treatment.

The present invention is further described by the following non-limiting Examples.

EXAMPLE 1

The differentiated human keratinocyte cell line, HaCaT [9] was used in the in vitro assay. Cells at passage numbers 33 to 36 were maintained as monolayer cultures in 5% V/V CO₂ at 37° C. in Keratinocyte-SFM (Gibco) containing EGF and bovine pituitary extract as supplied. Media containing foetal calf serum were avoided because of the high content of IGF-I binding proteins in serum.

Feeder layer plates of lethally irradiated 3T3 fibroblasts were prepared exactly as described by Rheinwald and Green [10].

EXAMPLE 2

Cells were grown to 4 days post confluence in 2 cm² wells with daily medium changes of Keratinocyte-SFM, then the medium was changed to DMEM (Cytosystems, Australia), with the following additions: 25 mM Hepes, 0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co, USA), 50IU/ml penicillin and 50 μg/ml streptomycin (Flow Laboratories). After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in 0.5 ml fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours. [³H]-Thymidine (0.1 μCi/well) was then added and the cells incubated for a further 3 hours. The medium was then aspirated and the cells washed once with ice-cold PBS and twice with ice-cold 10% v/v TCA. The TCA-precipitated monolayers were then solubilized with 0.25M NaOH (200 μl/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).

EXAMPLE 3

HaCaT conditioned medium (250 μl) was concentrated by adding 750 μl cold ethanol, incubating at −20° C. for 2 hours and centrifuging at 16,000 g for 20 min at 4° C. The resulting pellet was air dried, resuspended thoroughly in non-reducing Laemmli sample buffer, heated to 90° C. for 5 minutes and separated on 12% w/v SDS-PAGE according to the method of Laemmli (1970).

Separated proteins were electrophoretically transferred to nitrocellulose membrane (0.45 mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25 mM Tris, 192 mM glycine and 20% v/v methanol. IGFBPs were then visualised by the procedure of Hossenlopp et al [11], using [¹²⁵I]-IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.

EXAMPLE 4

Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Adelaide, South Australia, Australia. The following antisense sequences were used: BP3AS2, 5′-GCG CCC GCT GCA TGA CGC CTG CAA C-3′ (<400>4), a 25 mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, 5′-CGG GCG GCT CAC CTG GAG CTG GCG-3′ (<400>5), a 24 mer complementary to the exon 1/intron 1 splice site; BP3AS4, 5′-AGG CGG CTG ACG GCA CTA-3′(<400>6), an 18 mer complementary to a region of the coding sequence lacking RNA secondary structure and oligonucleotide-dimer formation (using the computer software “OLIGO for PC”). Since BP3AS4 was found to be ineffective at inhibiting IGFBP-3 synthesis, it was used as a control. The following additional control oligonucleotide sequences were used: BP3S, 5′-CAG GCG TCA TGC AGC GGG C-3′ (<400>7), an 18 mer sense control sequence equivalent to the start codon region; BP3AS2NS, 5′-CGG AGA TGC CGC ATG CCA GCG CAG G-3′ (<400>8), a 25 mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, 5′-GAC AGC GTC GGA GCG ATC-3′ (<400>9), an 18 mer randomised sequence with the same GC content as BP3AS4NS. Design of the oligonucleotides was based on the human IGFBP-3 cDNA sequence of Spratt et al [12].

Cells were grown to one day post confluence in 2 cm² wells with daily medium changes of 0.5 ml Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte-SFM for a further 4 days. Daily additions of 0.5 ml fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 5 μl oligonucleotide in PBS was added to give the final concentrations indicated, then the wells were shaken to mix the oligonucleotide. After the final addition, cells were incubated for 24 hours and the medium collected for assay of IGFBPs. Cells were then counted after trypsinisation in a Coulter Industrial D Counter, Coulter Bedfordshire, UK. Cell numbers after oligonucleotide treatment differed by less than 10%.

EXAMPLE 5

HaCaT cells secrete mainly IGFBP-3 (>95%), with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 (<5%). The effect on IGFBP-3 and IGFBP-4 synthesis of antisense oligonucleotides at two concentrations, 5 μM and 0.5 μM, was tested. Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in FIGS. 4A and 4B, all oligonucleotides at 5 μM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately 50% compared to the sense control (FIG. 4B). The antisense oligonucleotide directed to the start codon appeared to be more effective of the two, the difference being more apparent at the lower concentration of 0.5 μM. The cells of IGFBP-4 secreted by the HaCaT cells make photographic reproduction of the bands on Western ligand blots difficult, however densitometry measurements provide adequate relative quantitation. This resulted in the significant observation that IGFBP-4 levels were unaffected by oligonucleotide addition to the cells, suggesting that the observed inhibitory effects on IGFBP-3 are specific.

To further investigate the inhibitory effects of the more effective of the two antisense oligonucleotides, BP3AS2, inhibition by this oligonucleotide at 0.5 μM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5 μM. As shown in FIGS. 5A and 5B, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of BP3AS2. The other control oligonucleotides caused no reduction in IGFBP-3 levels at 0.5 μM, compared to untreated cells.

Of possible significance is the fact that this control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has the highest potential T_(m) of the three control oligonucleotides used in this experiment, enhancing the probability of non-specific base pairing with non-target mRNAs. However, the lack of inhibition of IGFBP-4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.

EXAMPLE 6

Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: ATTCGGGGCGAGGGA AGGAGGCGGCTCCCG CACCTGCCCGCCCGC TTCGGGGCGAGGGAG GGAGGCGGCTCCCGC ACCTGCCCGCCCGCC TCGGGGCGAGGGAGG GAGGCGGCTCCCGCT CCTGCCCGCCCGCCC CGGGGCGAGGGAGGA AGGCGGCTCCCGCTC CTGCCCGCCCGCCCG GGGGCGAGGGAGGAG GGCGGCTCCCGCTCG TGCCCGCCCGCCCGC GGGCGAGGGAGGAGG GCGGCTCCCGCTCGC GCCCGCCCGCCCGCT GGCGAGGGAGGAGGA CGGCTCCCGCTCGCA CCCGCCCGCCCGCTC GCGAGGGAGGAGGAA GGCTCCCGCTCGCAG CCGCCCGCCCGCTCG CGAGGGAGGAGGAAG GCTCCCGCTCGCAGG CGCCCGCCCGCTCGC GAGGGAGGAGGAAGA CTCCCGCTCGCAGGG GCCCGCCCGCTCGCT AGGGAGGAGGAAGAA TCCCGCTCGCAGGGC CCCGCCCGCTCGCTC GGGAGGAGGAAGAAG CCCGCTCGCAGGGCC CCGCCCGCTCGCTCG GGAGGAGGAAGAAGC CCGCTCGCAGGGCCG CGCCCGCTCGCTCGC GAGGAGGAAGAAGCG CGCTCGCAGGGCCGT GCCCGCTCGCTCGCT AGGAGGAAGAAGCGG GCTCGCAGGGCCGTG CCCGCTCGCTCGCTC GGAGGAAGAAGCGGA CTCGCAGGGCCGTGC CCGCTCGCTCGCTCG GAGGAAGAAGCGGAG TCGCAGGGCCGTGCA CGCTCGCTCGCTCGC AGGAAGAAGCGGAGG CGCAGGGCCGTGCAC GCTCGCTCGCTCGCC GGAAGAAGCGGAGGA GCAGGGCCGTGCACC CTCGCTCGCTCGCCC GAAGAAGCGGAGGAG CAGGGCCGTGCACCT TCGCTCGCTCGCCCG AAGAAGCGGAGGAGG AGGGCCGTGCACCTG CGCTCGCTCGCCCGC AGAAGCGGAGGAGGC GGGCCGTGCACCTGC GCTCGCTCGCCCGCC GAAGCGGAGGAGGCG GGCCGTGCACCTGCC CTCGCTCGCCCGCCG AAGCGGAGGAGGCGG GCCGTGCACCTGCCC TCGCTCGCCCGCCGC AGCGGAGGAGGCGGC CCGTGCACCTGCCCG CGCTCGCCCGCCGCG GCGGAGGAGGCGGCT CGTGCACCTGCCCGC GCTCGCCCGCCGCGC CGGAGGAGGCGGCTC GTGCACCTGCCCGCC CTCGCCCGCCGCGCC GGAGGAGGCGGCTCC TGCACCTGCCCGCCC TCGCCCGCCGCGCCG GAGGAGGCGGCTCCC GCACCTGCCCGCCCG CGCCCGCCGCGCCGC GCCCGCCGCGCCGCG GGGCTGCCCCGCGCT TGCTGCCGCTGCTGC CCCGCCGCGCCGCGC GGCTGCCCCGCGCTG GCTGCCGCTGCTGCT CCGCCGCGCCGCGCT GCTGCCCCGCGCTGC CTGCCGCTGCTGCTG CGCCGCGCCGCGCTG CTGCCCCGCGCTGCC TGCCGCTGCTGCTGC GCCGCGCCGCGCTGC TGCCCCGCGCTGCCG GCCGCTGCTGCTGCT CCGCGCCGCGCTGCC GCCCCGCGCTGCCGC CCGCTGCTGCTGCTG CGCGCCGCGCTGCCG CCCCGCGCTGCCGCT CGCTGCTGCTGCTGC GCGCCGCGCTGCCGA CCCGCGCTGCCGCTG GCTGCTGCTGCTGCT CGCCGCGCTGCCGAC CCGCGCTGCCGCTGC CTGCTGCTGCTGCTA GCCGCGCTGCCGACC CGCGCTGCCGCTGCC TGCTGCTGCTGCTAC CCGCGCTGCCGACCG GCGCTGCCGCTGCCG GCTGCTGCTGCTACT CGCGCTGCCGACCGC CGCTGCCGCTGCCGC CTGCTGCTGCTACTG GCGCTGCCGACCGCC GCTGCCGCTGCCGCC TGCTGCTGCTACTGG CGCTGCCGACCGCCA CTGCCGCTGCCGCCG GCTGCTGCTACTGGG GCTGCCGACCGCCAG TGCCGCTGCCGCCGC CTGCTGCTACTGGGC CTGCCGACCGCCAGC GCCGCTGCCGCCGCC TGCTGCTACTGGGCG TGCCGACCGCCAGCA CCGCTGCCGCCGCCG GCTGCTACTGGGCGC GCCGACCGCCAGCAT CGCTGCCGCCGCCGC CTGCTACTGGGCGCG CCGACCGCCAGCATG GCTGCCGCCGCCGCC TGCTACTGGGCGCGA CGACCGCCAGCATGC CTGCCGCCGCCGCCG GCTACTGGGCGCGAG GACCGCCAGCATGCT TGCCGCCGCCGCCGC CTACTGGGCGCGAGT ACCGCCAGCATGCTG GCCGCCGCCGCCGCT TACTGGGCGCGAGTG CCGCCAGCATGCTGC CCGCCGCCGCCGCTG ACTGGGCGCGAGTGG CGCCAGCATGCTGCC CGCCGCCGCCGCTGC CTGGGCGCGAGTGGC GCCAGCATGCTGCCG GCCGCCGCCGCTGCT TGGGCGCGAGTGGCG CCAGCATGCTGCCGA CCGCCGCCGCTGCTG GGGCGCGAGTGGCGG CAGCATGCTGCCGAG CGCCGCCGCTGCTGC GGCGCGAGTGGCGGC AGCATGCTGCCGAGA GCCGCCGCTGCTGCC GCGCGAGTGGCGGCG GCATGCTGCCGAGAG CCGCCGCTGCTGCCG CGCGAGTGGCGGCGG CATGCTGCCGAGAGT CGCCGCTGCTGCCGC GCGAGTGGCGGCGGC ATGCTGCCGAGAGTG GCCGCTGCTGCCGCT CGAGTGGCGGCGGCG TGCTGCCGAGAGTGG CCGCTGCTGCCGCTG GAGTGGCGGCGGCGG GCTGCCGAGAGTGGG CGCTGCTGCCGCTGC AGTGGCGGCGGCGGC CTGCCGAGAGTGGGC GCTGCTGCCGCTGCT GTGGCGGCGGCGGCG TGCCGAGAGTGGGCT CTGCTGCCGCTGCTG TGGCGGCGGCGGCGG GCCGAGAGTGGGCTG TGCTGCCGCTGCTGC GGCGGCGGCGGCGGG CCGAGAGTGGGCTGC GCTGCCGCTGCTGCC GCGGCGGCGGCGGGG CGAGAGTGGGCTGCC CTGCCGCTGCTGCCG CGGCGGCGGCGGGGC GAGAGTGGGCTGCCC TGCCGCTGCTGCCGC GGCGGCGGCGGGGCG AGAGTGGGCTGCCCC GCCGCTGCTGCCGCT GCGGCGGCGGGGCGC GAGTGGGCTGCCCCG CCGCTGCTGCCGCTG CGGCGGCGGGGCGCG AGTGGGCTGCCCCGC CGCTGCTGCCGCTGC GGCGGCGGGGCGCGC GTGGGCTGCCCCGCG GCTGCTGCCGCTGCT GCGGCGGGGCGCGCG TGGGCTGCCCCGCGC CTGCTGCCGCTGCTG CGGCGGGGCGCGCGC GGCGGGGCGCGCGCG ACCCGAGCGCCTGGC CCGCCGCGGTGGCCG GCGGGGCGCGCGCGG CCCGAGCGCCTGGCC CGCCGCGGTGGCCGC CGGGGCGCGCGCGGA CCGAGCGCCTGGCCG GCCGCGGTGGCCGCA GGGGCGCGCGCGGAG CGAGCGCCTGGCCGC CCGCGGTGGCCGCAG GGGCGCGCGCGGAGG GAGCGCCTGGCCGCC CGCGGTGGCCGCAGT GGCGCGCGCGGAGGT AGCGCCTGGCCGCCT GCGGTGGCCGCAGTG GCGCGCGCGGAGGTG GCGCCTGGCCGCCTG CGGTGGCCGCAGTGG CGCGCGCGGAGGTGC CGCCTGGCCGCCTGC GGTGGCCGCAGTGGC GCGCGCGGAGGTGCT GCCTGGCCGCCTGCG GTGGCCGCAGTGGCC CGCGCGGAGGTGCTG CCTGGCCGCCTGCGG TGGCCGCAGTGGCCG GCGCGGAGGTGCTGT CTGGCCGCCTGCGGG GGCCGCAGTGGCCGG CGCGGAGGTGCTGTT TGGCCGCCTGCGGGC GCCGCAGTGGCCGGA GCGGAGGTGCTGTTC GGCCGCCTGCGGGCC CCGCAGTGGCCGGAG CGGAGGTGCTGTTCC GCCGCCTGCGGGCCC CGCAGTGGCCGGAGG GGAGGTGCTGTTCCG CCGCCTGCGGGCCCC GCAGTGGCCGGAGGC GAGGTGCTGTTCCGC CGCCTGCGGGCCCCC CAGTGGCCGGAGGCG AGGTGCTGTTCCGCT GCCTGCGGGCCCCCG AGTGGCCGGAGGCGC GGTGCTGTTCCGCTG CCTGCGGGCCCCCGC GTGGCCGGAGGCGCC GTGCTGTTCCGCTGC CTGCGGGCCCCCGCC TGGCCGGAGGCGCCC TGCTGTTCCGCTGCC TGCGGGCCCCCGCCG GGCCGGAGGCGCCCG GCTGTTCCGCTGCCC GCGGGCCCCCGCCGG GCCGGAGGCGCCCGC CTGTTCCGCTGCCCG CGGGCCCCCGCCGGT CCGGAGGCGCCCGCA TGTTCCGCTGCCCGC GGGCCCCCGCCGGTT CGGAGGCGCCCGCAT GTTCCGCTGCCCGCC GGCCCCCGCCGGTTG GGAGGCGCCCGCATG TTCCGCTGCCCGCCC GCCCCCGCCGGTTGC GAGGCGCCCGCATGC TCCGCTGCCCGCCCT CCCCCGCCGGTTGCG AGGCGCCCGCATGCC CCGCTGCCCGCCCTG CCCCGCCGGTTGCGC GGCGCCCGCATGCCA CGCTGCCCGCCCTGC CCCGCCGGTTGCGCC GCGCCCGCATGCCAT GCTGCCCGCCCTGCA CCCCCGGTTGCGCCG CGCCCGCATGCCATG CTGCCCGCCCTGCAC CGCCGGTTGCGCCGC GCCCGCATGCCATGC TGCCCGCCCTGCACA GCCGGTTGCGCCGCC CCCGCATGCCATGCG GCCCGCCCTGCACAC CCGGTTGCGCCGCCC CCGCATGCCATGCGC CCCGCCCTGCACACC CGGTTGCGCCGCCCG CGCATGCCATGCGCG CCGCCCTGCACACCC GGTTGCGCCGCCCGC GCATGCCATGCGCGG CGCCCTGCACACCCG GTTGCGCCGCCCGCC CATGCCATGCGCGGA GCCCTGCACACCCGA TTGCGCCGCCCGCCG ATGCCATGCGCGGAG CCCTGCACACCCGAG TGCGCCGCCCGCCGC TGCCATGCGCGGAGC CCTGCACACCCGAGC GCGCCGCCCGCCGCG GCCATGCGCGGAGCT CTGCACACCCGAGCG CGCCGCCCGCCGCGG CCATGCGCGGAGCTC TGCACACCCGAGCGC GCCGCCCGCCGCGGT CATGCGCGGAGCTCG GCACACCCGAGCGCC CCGCCCGCCGCGGTG ATGCGCGGAGCTCGT CACACCCGAGCGCCT CGCCCGCCGCGGTGG TGCGCGGAGCTCGTC ACACCCGAGCGCCTG GCCCGCCGCGGTGGC GCGCGGAGCTCGTCC CACCCGAGCGCCTGG CCCGCCGCGGTGGCC CGCGGAGCTCGTCCG GCGGAGCTCGTCCGG CGCCCGGCTGGAGGG GCGGCCAGGGGCTGC CGGAGCTCGTCCGCG GCCCGGCTGGAGGGC CGGCCAGGGGCTGCG GGAGCTCGTCCGGGA CCCGGCTGGAGGGCG GGCCAGGGGCTGCGC GAGCTCGTCCGGGAG CCGGCTGGAGGGCGA GCCAGGGGCTGCGCT AGCTCGTCCGGGAGC CGGCTGGAGGGCGAG CCAGGGGCTGCGCTG GCTCGTCCGGGAGCC GGCTGGAGGGCGAGG CAGGGGCTGCGCTGC CTCGTCCGGGAGCCG GCTGGAGGGCGAGGC AGGGGCTGCGCTGCT TCGTCCGGGAGCCGG CTGGAGGGCGAGGCG GGGGCTGCGCTGCTA CGTCCGGGAGCCGGG TGGAGGGCGAGGCGT GGGCTGCGCTGCTAT GTCCGGGAGCCGGGC GGAGGGCGAGGCGTG GGCTGCGCTGCTATC TCCGGGAGCCGGGCT GAGGGCGAGGCGTGC GCTGCGCTGCTATCC CCGGGAGCCGGGCTG AGGGCGAGGCGTGCG CTGCGCTGCTATCCC CGGGAGCCGGGCTGC GGGCGAGGCGTGCGG TGCGCTGCTATCCCC GGGAGCCGGGCTGCG GGCGAGGCGTGCGGC GCGCTGCTATCCCCA GGAGCCGGGCTGCGG GCGAGGCGTGCGGCG CGCTGCTATCCCCAC GAGCCGGGCTGCGGC CGAGGCGTGCGGCGT GCTGCTATCCCCACC AGCCGGGCTGCGGCT GAGGCGTGCGGCGTC CTGCTATCCCCACCC GCCGGGCTGCGGCTG AGGCGTGCGGCGTCT TGCTATCCCCACCCG CCGGGCTGCGGCTGC GGCGTGCGGCGTCTA GCTATCCCCACCCGG CGGGCTGCGGCTGCT GCGTGCGGCGTCTAC CTATCCCCACCCGGG GGGCTGCGGCTGCTG CGTGCGGCGTCTACA TATCCCCACCCGGGC GGCTGCGGCTGCTGC GTGCGGCGTCTACAC ATCCCCACCCGGGCT GCTGCGGCTGCTGCT TGCGGCGTCTACACC TCCCCACCCGGGCTC CTGCGGCTGCTGCTC GCGGCGTCTACACCC CCCCACCCGGGCTCC TGCGGCTGCTGCTCG CGGCGTCTACACCCC CCCACCCGGGCTCCG GCGGCTGCTGCTCGG GGCGTCTACACCCCG CCACCCGGGCTCCGA CGGCTGCTGCTCGGT GCGTCTACACCCCGC CACCCGGGCTCCGAG GGCTGCTGCTCGGTG CGTCTACACCCCGCG ACCCGGGCTCCGAGC GCTGCTGCTCGGTGT GTCTACACCCCGCGC CCCGGGCTCCGAGCT CTGCTGCTCGGTGTG TCTACACCCCGCGCT CCGGGCTCCGAGCTG TGCTGCTCGGTGTGC CTACACCCCGCGCTG CGGGCTCCGAGCTGC GCTGCTCGGTGTGCG TACACCCCGCGCTGC GGGCTCCGAGCTGCC CTGCTCGGTGTGCGC ACACCCCGCGCTGCG GGCTCCGAGCTGCCC TGCTCGGTGTGCGCC CACCCCGCGCTGCGG GCTCCGAGCTGCCCC GCTCGGTGTGCGCCC ACCCCGCGCTGCGGC CTCCGAGCTGCCCCT CTCGGTGTGCGCCCG CCCCGCGCTGCGGCC TCCGAGCTGCCCCTG TCGGTGTGCGCCCGG CCCGCGCTGCGGCCA CCGAGCTGCCCCTGC CGGTGTGCGCCCGGC CCGCGCTGCGGCCAG CGAGCTGCCCCTGCA GGTGTGCGCCCGGCT CGCGCTGCGGCCAGG GAGCTGCCCCTGCAG GTGTGCGCCCGGCTG GCGCTGCGGCCAGGG AGCTGCCCCTGCAGG TGTGCGCCCGGCTGG CGCTGCGGCCAGGGG GCTGCCCCTGCAGGC GTGCGCCCGGCTGGA GCTGCGGCCAGGGGC CTGCCCCTGCAGGCG TGCGCCCGGCTGGAG CTGCGGCCAGGGGCT TGCCCCTGCAGGCGC GCGCCCGGCTGGAGG TGCGGCCAGGGGCTG GCCCCTGCAGGCGCT CCCCTGCAGGCGCTG CCGGGACGCCGAGTA ATGGCGATGACCACT CCCTGCAGGCGCTGG CGGGACGCCGAGTAT TGGCGATGACCACTC CCTGCAGGCGCTGGT GGGACGCCGAGTATG GGCGATGACCACTCA CTGCAGGCGCTGGTC GGACGCCGAGTATGG GCGATGACCACTCAG TGCAGGCGCTGGTCA GACGCCGAGTATGGC CGATGACCACTCAGA GCAGGCGCTGGTCAT ACGCCGAGTATGGCG GATGACCACTCAGAA CAGGCGCTGGTCATG CGCCGAGTATGGCGC ATGACCACTCAGAAG AGGCGCTGGTCATGG GCCGAGTATGGCGCC TGACCACTCAGAAGG GGCGCTGGTCATGGG CCGAGTATGGCGCCA GACCACTCAGAAGGA GCGCTGGTCATGGGC CGAGTATGGCGCCAG ACCACTCAGAAGGAG CGCTGGTCATGGGCG GAGTATGGCGCCAGC CCACTCAGAAGGAGG GCTGGTCATGGGCGA AGTATGGCGCCAGCC CACTCAGAAGGAGGC CTGGTCATGGGCGAG GTATGGCGCCAGCCC ACTCAGAAGGAGGCC TGGTCATGGGCGAGG TATGGCGCCAGCCCG CTCAGAAGGAGGCCT GGTCATGGGCGAGGG ATGGCGCCAGCCCGG TCAGAAGGAGGCCTG GTCATGGGCGAGGGC TGGCGCCAGCCCGGA CAGAAGGAGGCCTGG TCATGGGCGAGGGCA GGCGCCAGCCCGGAG AGAAGGAGGCCTGGT CATGGGCGAGGGCAC GCGCCAGCCCGGAGC GAAGGAGGCCTGGTG ATGGGCGAGGGCACT CGCCAGCCCGGAGCA AAGGAGGCCTGGTGG TGGGCGAGGGCACTT GCCAGCCCGGAGCAG AGGAGGCCTGGTGGA GGGCGAGGGCACTTG CCAGCCCGGAGCAGG GGAGGCCTGGTGGAG GGCGAGGGCACTTGT CAGCCCGGAGCAGGT GAGGCCTGGTGGAGA GCGAGGGCACTTGTG AGCCCGGAGCAGGTT AGGCCTGGTGGAGAA CGAGGGCACTTGTGA GCCCGGAGCAGGTTG GGCCTGGTGGAGAAC GAGGGCACTTGTGAG CCCGGAGCAGGTTGC GCCTGGTGGAGAACC AGGGCACTTGTGAGA CCGGAGCAGGTTGCA CCTGGTGGAGAACCA GGGCACTTGTGAGAA CGGAGCAGGTTGCAG CTGGTGGAGAACCAC GGCACTTGTGAGAAG GGAGCAGGTTGCAGA TGGTGGAGAACCACG GCACTTGTGAGAAGC GAGCAGGTTGCAGAC GGTGGAGAACCACGT CACTTGTGAGAAGCG AGCAGGTTGCAGACA GTGGAGAACCACGTG ACTTGTGAGAAGCGC GCAGGTTGCAGACAA TGGAGAACCACGTGG CTTGTGAGAAGCGCC CAGGTTGCAGACAAT GGAGAACCACGTGGA TTGTGAGAAGCGCCG AGGTTGCAGACAATG GAGAACCACGTGGAC TGTGAGAAGCGCCGG GGTTGCAGACAATGG AGAACCACGTGGACA GTGAGAAGCGCCGGG GTTGCAGACAATGGC GAACCACGTGGACAG TGAGAAGCGCCGGGA TTGCAGACAATGGCG AACCACGTGGACAGC GAGAAGCGCCGGGAC TGCAGACAATGGCGA ACCACGTGGACAGCA AGAAGCGCCGGGACG GCAGACAATGGCGAT CCACGTGGACAGCAC GAAGCGCCGGGACGC CAGACAATGGCGATG CACGTGGACAGCACC AAGCGCCGGGACGCC AGACAATGGCGATGA ACGTGGACAGCACCA AGCGCCGGGACGCCG GACAATGGCGATGAC CGTGGACAGCACCAT GCGCCGGGACGCCGA ACAATGGCGATGACC GTGGACAGCACCATG CGCCGGGACGCCGAG CAATGGCGATGACCA TGGACAGCACCATGA GCCGGGACGCCGAGT AATGGCGATGACCAC GGACAGCACCATGAA GACAGCACCATGAAC GAAGCCCCTCAAGTC AGAAGGTCACTGAGC ACAGCACCATGAACA AAGCCCCTCAAGTCG GAAGGTCACTGAGCA CAGCACCATGAACAT AGCCCCTCAAGTCGG AAGGTCACTGAGCAG AGCACCATGAACATG GCCCCTCAAGTCGGG AGGTCACTGAGCAGC GCACCATGAACATGT CCCCTCAAGTCGGGT GGTCACTGAGCAGCA CACCATGAACATGTT CCCTCAAGTCGGGTA GTCACTGAGCAGCAC ACCATGAACATGTTG CCTCAAGTCGGGTAT TCACTGAGCAGCACC CCATGAACATGTTGG CTCAAGTCGGGTATG CACTGAGCAGCACCG CATGAACATGTTGGG TCAAGTCGGGTATGA ACTGAGCAGCACCGG ATGAACATGTTGGGC CAAGTCGGGTATGAA CTGAGCAGCACCGGC TGAACATGTTGGGCG AAGTCGGGTATGAAG TGAGCAGCACCGGCA GAACATGTTGGGCGG AGTCGGGTATGAAGG GAGCAGCACCGGCAG AACATGTTGGGCGGG GTCGGGTATGAAGGA AGCAGCACCGGCAGA ACATGTTGGGCGGGG TCGGGTATGAAGGAG GCAGCACCGGCAGAT CATGTTGGGCGGGGG CGGGTATGAAGGAGC CAGCACCGGCAGATG ATGTTGGGCGGGGGA GGGTATGAAGGAGCT AGCACCGGCAGATGG TGTTGGGCGGGGGAG GGTATGAAGGAGCTG GCACCGGCAGATGGG GTTGGGCGGGGGAGG GTATGAAGGAGCTGG CACCGGCAGATGGGC TTGGGCGGGGGAGGC TATGAAGGAGCTGGC ACCGGCAGATGGGCA TGGGCGGGGGAGGCA ATGAAGGAGCTGGCC CCGGCAGATGGGCAA GGGCGGGGGAGGCAG TGAAGGAGCTGGCCG CGGCAGATGGGCAAG GGCGGGGGAGGCAGT GAAGGAGCTGGCCGT GGCAGATGGGCAAGG GCGGGGGAGGCAGTG AAGGAGCTGGCCGTG GCAGATGGGCAAGGG CGGGGGAGGCAGTGC AGGAGCTGGCCGTGT CAGATGGGCAAGGGT GGGGGAGGCAGTGCT GGAGCTGGCCGTGTT AGATGGGCAAGGGTG GGGGAGGCAGTGCTG GAGCTGGCCGTGTTC GATGGGCAAGGGTGG GGGAGGCAGTGCTGG AGCTGGCCGTGTTCC ATGGGCAAGGGTGGC GGAGGCAGTGCTGGC GCTGGCCGTGTTCCG TGGGCPAGGGTGGCA GAGGCAGTGCTGGCC CTGGCCGTGTTCCGG GGGCAAGGGTGGCAA AGGCAGTGCTGGCCG TGGCCGTGTTCCGGG GGCAAGGGTGGCAAG GGCAGTGCTGGCCGG GGCCGTGTTCCGGGA GCAAGGGTGGCAAGC GCAGTGCTGGCCGGA GCCGTGTTCCGGGAG CAAGGGTGGCAAGCA CAGTGCTGGCCGGAA CCGTGTTCCGGGAGA AAGGGTGGCAAGCAT AGTGCTGGCCGGAAG CGTGTTCCGGGAGAA AGGGTGGCAAGCATC GTGCTGGCCGGAAGC GTGTTCCGGGAGAAG GGGTGGCAAGCATCA TGCTGGCCGGAAGCC TGTTCCGGGAGAAGG GGTGGCAAGCATCAC GCTGGCCGGAAGCCC GTTCCGGGAGAAGGT GTGGCAAGCATCACC CTGGCCGGAAGCCCC TTCCGGGAGAAGGTC TGGCAAGCATCACCT TGGCCGGAAGCCCCT TCCGGGAGAAGGTCA GGCAAGCATCACCTT GGCCGGAAGCCCCTC CCGGGAGAAGGTCAC GCAAGCATCACCTTG GCCGGAAGCCCCTCA CGGGAGAAGGTCACT CAAGCATCACCTTGG CCGGAAGCCCCTCAA GGGAGAAGGTCACTG AAGCATCACCTTGGC CGGAAGCCCCTCAAG GGAGAAGGTCACTGA AGCATCACCTTGGCC GGAAGCCCCTCAAGT GAGAAGGTCACTGAG GCATCACCTTGGCCT CATCACCTTGGCCTG TGCCAGGACTCCCTG GGATCTCCACCATGC ATCACCTTGGCCTGG GCCAGGACTCCCTGC GATCTCCACCATGCG TCACCTTGGCCTCGA CCAGGACTCCCTGCC ATCTCCACCATGCGC CACCTTGGCCTGGAG CAGGACTCCCTGCCA TCTCCACCATGCGCC ACCTTGGCCTGGAGG AGGACTCCCTGCCAA CTCCACCATGCGCCT CCTTGGCCTGGAGGA GGACTCCCTGCCAAC TCCACCATGCGCCTT CTTGGCCTGGAGGAG GACTCCCTGCCAACA CCACCATGCGCCTTC TTGGCCTGGAGGAGC ACTCCCTGCCAACAG CACCATGCGCCTTCC TGGCCTGGAGGAGCC CTCCCTGCCAACAGG ACCATGCGCCTTCCG GGCCTGGAGGAGCCC TGCCTGCCAACAGGA GGATGCGCCTTCCGG GCCTGGAGGACCCCA GCCTGCCAACAGGAA CATGCGCCTTCCGGA CCTGGAGGAGCCCAA CCTGCCAACAGGAAC ATGCGCCTTCCGGAT CTGGAGGAGCCCAAG CTGCCAACAGGAACT TGCGCCTTCCGGATG TGGAGGAGCCCAAGA TGCCAACAGGAACTG GCGCCTTCCGGATGA GGAGGAGCCCAAGAA GCCAACAGGAACTGG CGCCTTCCGGATGAG GAGGAGCCCAAGAAG CCAACAGGAACTGGA GCCTTCCGGATGAGC AGGAGCCCAAGAAGC CAACAGGAACTGGAC CCTTCCGGATGAGCG GGAGCCCAAGAAGCT AACAGGAACTGGACC CTTCCGGATGAGCGG GAGCCCAAGAAGCTG ACAGGAACTGGACCA TTCCGGATGAGCGGG AGCCCAAGAAGCTGC CAGGAACTGGACCAG TCCGGATGAGCGGGG GCCCAAGAAGCTGCG AGGAACTGGACCAGG CCGGATGAGCGGGGC CCCAAGAAGCTGCGA GGAACTGGACCAGGT CGGATGAGCGGGGCC CCAAGAAGCTGCGAC GAACTGGACCAGGTC GGATGAGCGGGGCCC CAAGAAGCTGCGACC AACTGGACCAGGTCC GATGAGCGGGGCCCT AAGAAGCTGCGACCA ACTGGACCAGGTCCT ATGAGCGGGGCCCTC AGAAGCTGCGACCAC CTGGACCAGGTCCTG TGAGCGGGGCCCTCT GAAGCTGCGACCACC TGGACCAGGTCCTGG GAGCGGGGCCCTCTG AAGCTGCGACCACCC GGACCAGGTCCTGGA AGCGGGGCCCTCTGG AGCTGCGACCACCCC GACCAGGTCCTGGAG GCGGGGCCCTCTGGA GCTGCGACCACCCCC ACCAGGTCCTGGAGC CGGGGCCCTCTGGAG CTGCGACCACCCCCT CCAGGTCCTGGAGCG GGGGCCCTCTGGAGC TGCGACCACCCCCTG CAGGTCCTGGAGCGG GGGCCCTCTGGAGCA GCGACCACCCCCTGC AGGTCCTGGAGCGGA GGCCCTCTGGAGCAC CGACCACCCCCTGCC GGTCCTGGAGCGGAT GCCCTCTGGAGCACC GACCACCCCCTGCCA GTCCTGGAGCGGATC CCCTCTGGAGCACCT ACCACCCCCTGCCAG TCCTGGAGCGGATCT CCTCTGGAGCACCTC CCACCCCCTGCCAGG CCTGGAGCGGATCTC CTCTGGAGCACCTCT CACCCCCTGCCAGGA CTGGAGCGGATCTCC TCTGGAGCACCTCTA ACCCCCTGCCAGGAC TGGAGCGGATCTCCA CTGGAGCACCTCTAC CCCCCTGCCAGGACT GGAGCGGATCTCCAC TGGAGCACCTCTACT CCCCTGCCAGGACTC GAGCGGATCTCCACC GGAGCACCTCTACTC CCCTGCCAGGACTCC AGCGGATCTCCACCA GAGCACCTCTACTCC CCTGCCAGGACTCCC GCGGATCTCCACCAT AGCACCTCTACTCCC CTGCCAGGACTCCCT CGGATCTCCACCATG GCACCTCTACTCCCT CACCTCTACTCCCTG GTACAACCTCAAACA GGGAGTGCTGGTGTG ACCTCTACTCCCTGC TACAACCTCAAACAG GGAGTGCTGGTGTGT CCTCTACTCCCTGCA ACAACCTCAAACAGT GAGTGCTGGTGTGTG CTCTACTCCCTGCAC CAACCTCAAACAGTG AGTGCTGGTGTGTGA TCTACTCCCTGCACA AACCTCAAACAGTGC GTGCTGGTGTGTGAA CTACTCCCTGCACAT ACCTCAAACAGTGCA TGCTGGTGTGTGAAC TACTCCCTGCACATC CCTCAAACAGTGCAA GCTGGTGTGTGAACC ACTCCCTGCACATCC CTCAAACAGTGCAAG CTGGTGTGTGAACCC CTCCCTGCACATCCC TCAAACAGTGCAAGA TGGTGTGTGAACCCC TCCCTGCACATCCCC CAAACAGTGCAAGAT GGTGTGTGAACCCCA CCCTGCACATCCCCA AAACAGTGCAAGATG GTGTGTGAACCCCAA CCTGCACATCCCCAA AACAGTGCAAGATGT TGTGTGAACCCCAAC CTGCACATCCCCAAC ACAGTGCAAGATGTC GTGTGAACCCCAACA TGCACATCCCCAACT CAGTGCAAGATGTCT TGTGAACCCCAACAC GCACATCCCCAACTG AGTGCAAGATGTCTC GTGAACCCCAACACC CACATCCCCAACTGT GTGCAAGATGTCTCT TGAACCCCAACACCG ACATCCCCAACTGTG TGCAAGATGTCTCTG GAACCCCAACACCGG CATCCCCAACTGTGA GCAAGATGTCTCTGA AACCCCAACACCGGG ATCCCCAACTGTGAC CAAGATGTCTCTGAA ACCCCAACACCGGGA TCCCCAACTGTGACA AAGATGTCTCTGAAC CCCCAACACCGGGAA CCCCAACTGTGACAA AGATGTCTCTGAACG CCCAACACCGGGAAG CCCAACTGTGACAAG GATGTCTCTGAACGG CCAACACCGGGAAGC CCAACTGTGACAAGC ATGTCTCTGAACGGG CAACACCGGGAAGCT CAACTGTGACAAGCA TGTCTCTGAACGGGC AACACCGGGAAGCTG AACTGTGACAAGCAT GTCTCTGAACGGGCA ACACCGGGAAGCTGA ACTGTGACAAGCATG TCTCTGAACGGGCAG CACCGGGAAGCTGAT CTGTGACAAGCATGG CTCTGAACGGGCAGC ACCGGGAAGCTGATC TGTGACAAGCATGGC TCTGAACGGGCAGCG CCGGGAAGCTGATCC GTGACAAGCATGGCC CTGAACGGGCAGCGT CGGGAAGCTGATCCA TGACAAGCATGGCCT TGAACGGGCAGCGTG GGGAAGCTGATCCAG GACAAGCATGGCCTG GAACGGGCAGCGTGG GGAAGCTGATCCAGG ACAAGCATGGCCTGT AACGGGCAGCGTGGG GAAGCTGATCCAGGG CAAGCATGGCCTGTA ACGGGCAGCGTGGGG AAGCTGATCCAGGGA AAGCATGGCCTGTAC CGGGCAGCGTGGGGA AGCTGATCCAGGGAG AGCATGGCCTGTACA GGGCAGCGTGGGGAG GCTGATCCAGGGAGC GCATGGCCTGTACAA GGCAGCGTGGGGAGT CTGATCCAGGGAGCC CATGGCCTGTACAAC GCAGCGTGGGGAGTG TGATCCAGGGAGCCC ATGGCCTGTACAACC CAGCGTGGGGAGTGC GATCCAGGGAGCCCC TGGCCTGTACAACCT AGCGTGGGGAGTGCT ATCCAGGGAGCCCCC GGCCTGTACAACCTC GCGTGGGGAGTGCTG TCCAGGGAGCCCCCA GCCTGTACAACCTCA CGTGGGGAGTGCTGG CCAGGGAGCCCCCAC CCTGTACAACCTCAA GTGGGGAGTGCTGGT CAGGGAGCCCCCACC CTGTACAACCTCAAA TGGGGAGTGCTGGTG AGGGAGCCCCCACCA TGTACAACCTCAAAC GGGGAGTGCTGGTGT GGGAGCCCCCACCAT GGAGCCCCCACCATC CAATGAGCAGCAGGA AGTAGACCGCAGCCA GAGCCCCCACCATCC AATGAGCAGCAGGAG GTAGACCGCAGCCAG AGCCCCCACCATCCG ATGAGCAGCAGGAGG TAGACCGCAGCCAGC GCCCCCACCATCCGG TGAGCAGCAGGAGGC AGACCGCAGCCAGCC CCCCCACCATCCGGG GAGCAGCAGGAGGCT GACCGCAGCCAGCCG CCCCACCATCCGGGG AGCAGCAGGAGGCTT ACCGCAGCCAGCCGG CCCACCATCCGGGGG GCAGCAGGAGGCTTG CCGCAGCCAGCCGGT CCACCATCCGGGGGG CAGCAGGAGGCTTGC CGCAGCCAGCCGGTG CACCATCCGGGGGGA AGCAGGAGGCTTGCG GCAGCCAGCCGGTGC ACCATCCGGGGGGAC GCAGGAGGCTTGCGG CAGCCAGCCGGTGCC CCATCCGGGGGGACC CAGGAGGCTTGCGGG AGCCAGCCGGTGCCT CATCCGGGGGGACCC AGGAGGCTTGCGGGG GCCAGCCGGTGCCTG ATCCGGGGGGACCCC GGAGGCTTGCGGGGT CCAGCCGGTGCCTGG TCCGGGGGGACCCCG GAGGCTTGCGGGGTG CAGCCGGTGCCTGGC CCGGGGGGACCCCGA AGGCTTGCGGGGTGC AGCCGGTGCCTGGCG CGGGGGGACCCCGAG GGCTTGCGGGGTGCA GCCGGTGCCTGGCGC GGGGGGACCCCGAGT GCTTGCGGGGTGCAC CCGGTGCCTGGCGCC GGGGGACCCCGAGTG CTTGCGGGGTGCACA CGGTGCCTGGCGCCC GGGGACCCCGAGTGT TTGCGGGGTGCACAC GGTGCCTGGCGCCCC GGGACCCCGAGTGTC TGCGGGGTGCACACC GTGCCTGGCGCCCCT GGACCCCGAGTGTCA GCGGGGTGCACACCC TGCCTGGCGCCCCTG GACCCCGAGTGTCAT CGGGGTGCACACCCA GCCTGGCGCCCCTGC ACCCCGAGTGTCATC GGGGTGCACACCCAG CCTGGCGCCCCTGCC CCCCGAGTGTCATCT GGGTGCACACCCAGC CTGGCGCCCCTGCCC CCCGAGTGTCATCTC GGTGCACACCCAGCG TGGCGCCCCTGCCCC CCGAGTGTCATCTCT GTGCACACCCAGCGG GGCGCCCCTGCCCCC CGAGTGTCATCTCTT TGCACACCCAGCGGA GCGCCCCTGCCCCCC GAGTGTCATCTCTTC GCACACCCAGCGGAT CGCCCCTGCCCCCCG AGTGTCATCTCTTCT CACACCCAGCGGATG GCCCCTGCCCCCCGC GTGTCATCTCTTCTA ACACCCAGCGGATGC CCCCTGCCCCCCGCC TGTCATCTCTTCTAC CACCCAGCGGATGCA CCCTGCCCCCCGCCC GTCATCTCTTCTACA ACCCAGCGGATGCAG CCTGCCCCCCGCCCC TCATCTCTTCTACAA CCCAGCGGATGCAGT CTGCCCCCCGCCCCT CATCTCTTCTACAAT CCAGCGGATGCAGTA TGCCCCCCGCCCCTC ATCTCTTCTACAATG CAGCGGATGCAGTAG GCCCCCCGCCCCTCT TCTCTTCTACAATGA AGCGGATGCAGTAGA CCCCCCGCCCCTCTC CTCTTCTACAATGAG GCGGATGCAGTAGAC CCCCCGCCCCTCTCC TCTTCTACAATGAGC CGGATGCAGTAGACC CCCCGCCCCTCTCCA CTTCTACAATGAGCA GGATGCAGTAGACCG CCCGCCCCTCTCCAA TTCTACAATGAGCAG GATGCAGTAGACCGC CCGCCCCTCTCCAAA TCTACAATGAGCAGC ATGCAGTAGACCGCA CGCCCCTCTCCAAAC CTACAATGAGCAGCA TGCAGTAGACCGCAG GCCCCTCTCCAAACA TACAATGAGCAGCAG GCAGTAGACCGCAGC CCCCTCTCCAAACAC ACAATGAGCAGCAGG CAGTAGACCGCAGCC CCCTCTCCAAACACC CCTCTCCAAACACCG GTGCTGGAGGATTTT AAAGAGACCAGCACC CTCTCCAAACACCGG TGCTGGAGGATTTTC AAGAGACCAGCACCG TCTCCAAACACCGGC GCTGGAGGATTTTCC AGAGACCAGCACCGA CTCCAAACACCGGCA CTGGAGGATTTTCCA GAGACCAGCACCGAG TCCAAACACCGGCAG TGGAGGATTTTCCAG AGACCAGCACCGAGC CCAAACACCGGCAGA GGAGGATTTTCCAGT GACCAGCACCGAGCT CAAACACCGGCAGAA GAGGATTTTCCAGTT ACCAGCACCGAGCTC AAACACCGGCAGAAA AGGATTTTCCAGTTC CCAGCACCGAGCTCG AACACCGGCAGAAAA GGATTTTCCAGTTCT CAGCACCGAGCTCGG ACACCGGCAGAAAAC GATTTTCCAGTTCTG AGCACCGAGCTCGGC CACCGGCAGAAAACG ATTTTCCAGTTCTGA GCACCGAGCTCGGCA ACCGGCAGAAAACGG TTTTCCAGTTCTGAC CACCGAGCTCGGCAC CCGGCAGAAAACGGA TTTCCAGTTCTGACA ACCGAGCTCGGCACC CGGCAGAAAACGGAG TTCCAGTTCTGACAC CCGAGCTCGGCACCT GGCAGAAAACGGAGA TCCAGTTCTGACACA CGAGCTCGGCACCTC GCAGAAAACGGAGAG CCAGTTCTGACACAC GAGCTCGGCACCTCC CAGAAAACGGAGAGT CAGTTCTGACACACG AGCTCGGCACCTCCC AGAAAACGGAGAGTG AGTTCTGACACACGT GCTCGGCACCTCCCC GAAAACGGAGAGTGC GTTCTGACACACGTA CTCGGCACCTCCCCG AAAACGGAGAGTGCT TTCTGACACACGTAT TCGGCACCTCCCCGG AAACGGAGAGTGCTT TCTGACACACGTATT CGGCACCTCCCCGGC AACGGAGAGTGCTTG CTGACACACGTATTT GGCACCTCCCCGGCC ACGGAGAGTGCTTGG TGACACACGTATTTA GCACCTCCCCGGCCT CGGAGAGTGCTTGGG GACACACGTATTTAT CACCTCCCCGGCCTC GGAGAGTGCTTGGGT ACACACGTATTTATA ACCTCCCCGGCCTCT GAGAGTGCTTGGGTG CACACGTATTTATAT CCTCCCCGGCCTCTC AGAGTGCTTGGGTGG ACACGTATTTATATT CTCCCCGGCCTCTCT GAGTGCTTGGGTGGT CACGTATTTATATTT TCCCCGGCCTCTCTC AGTGCTTGGGTGGTG ACGTATTTATATTTG CCCCGGCCTCTCTCT GTGCTTGGGTGGTGG CGTATTTATATTTGG CCCGGCCTCTCTCTT TGCTTGGGTGGTGGG GTATTTATATTTGGA CCGGCCTCTCTCTTC GCTTGGGTGGTGGGT TATTTATATTTGGAA CGGCCTCTCTCTTCC CTTGGGTGGTGGGTG ATTTATATTTGGAAA GGCCTCTCTCTTCCC TTGGGTGGTGGGTGC TTTATATTTGGAAAG GCCTCTCTCTTCCCA TGGGTGGTGGGTGCT TTATATTTGGAAAGA CCTCTCTCTTCCCAG GGGTGGTGGGTGCTG TATATTTGGAAAGAG CTCTCTCTTCCCAGC GGTGGTGGGTGCTGG ATATTTGGAAAGAGA TCTCTCTTCCCAGCT GTGGTGGGTGCTGGA TATTTGGAAAGAGAC CTCTCTTCCCAGCTG TGGTGGGTGCTGGAG ATTTGGAAAGAGACC TCTCTTCCCAGCTGC GGTGGGTGCTGGAGG TTTGGAAAGAGACCA CTCTTCCCAGCTGCA GTGGGTGCTGGAGGA TTGGAAAGAGACCAG TCTTCCCAGCTGCAG TGGGTGCTGGAGGAT TGGAAAGAGACCAGC CTTCCCAGCTGCAGA GGGTGCTGGAGGATT GGAAAGAGACCAGCA TTCCCAGCTGCAGAT GGTGCTGGAGGATTT GAAAGAGACCAGCAC TCCCAGCTGCAGATG CCCAGCTGCAGATGC GGAGGAAGGGGGTTG GAGGGGGAAGAGAAA CCAGCTGCAGATGCC GAGGAAGGGGGTTGT AGGGGGAAGAGAAAT CAGCTGCAGATGCCA AGGAAGGGGGTTGTG GGGGGAAGAGAAATT AGCTGCAGATGCCAC GGAAGGGGGTTGTGG GGGGAAGAGAAATTT GCTGCAGATGCCACA GAAGGGGGTTGTGGT GGGAAGAGAAATTTT CTGCAGATGCCACAC AAGGGGGTTGTGGTC GGAAGAGAAATTTTT TGCAGATGCCACACC AGGGGGTTGTGGTCG GAAGAGAAATTTTTA GCAGATGCCACACCT GGGGGTTGTGGTCGG AAGAGAAATTTTTAT CAGATGCCACACCTG GGGGTTGTGGTCGGG AGAGAAATTTTTATT AGATGCCACACCTGC GGGTTGTGGTCGGGG GAGAAATTTTTATTT GATGCCACACCTGCT GGTTGTGGTCGGGGA AGAAATTTTTATTTT ATGCCACACCTGCTC GTTGTGGTCGGGGAG GAAATTTTTATTTTT TGCCACACCTGCTCC TTGTGGTCGGGGAGC AAATTTTTATTTTTG GCCACACCTGCTCCT TGTGGTCGGGGAGCT AATTTTTATTTTTGA CCACACCTGCTCCTT GTGGTCGGGGAGCTG ATTTTTATTTTTGAA CACACCTGCTCCTTC TGGTCGGGGAGCTGG TTTTTATTTTTGAAC ACACCTGCTCCTTCT GGTCGGGGAGCTGGG TTTTATTTTTGAACC CACCTGCTCCTTCTT GTCGGGGAGCTGGGG TTTATTTTTGAACCC ACCTGCTCCTTCTTG TCGGGGAGCTGGGGT TTATTTTTGAACCCC CCTGCTCCTTCTTGC CGGGGAGCTGGGGTA TATTTTTGAACCCCT CTGCTCCTTCTTGCT GGGGAGCTGGGGTAC ATTTTTGAACCCCTG TGCTCCTTCTTGCTT GGGAGCTGGGGTACA TTTTTGAACCCCTGT GCTCCTTCTTGCTTT GGAGCTGGGGTACAG TTTTGAACCCCTGTG CTCCTTCTTGCTTTC GAGCTGGGGTACAGG TTTGAACCCCTGTGT TCCTTCTTGCTTTCC AGCTGGGGTACAGGT TTGAACCCCTGTGTC CCTTCTTGCTTTCCC GCTGGGGTACAGGTT TGAACCCCTGTGTCC CTTCTTGCTTTCCCC CTGGGGTACAGGTTT GAACCCCTGTGTCCC TTCTTGCTTTCCCCG TGGGGTACAGGTTTG AACCCCTGTGTCCCT TCTTGCTTTCCCCGG GGGGTACAGGTTTGG ACCCCTGTGTCCCTT CTTGCTTTCCCCGGG GGGTACAGGTTTGGG CCCCTGTGTCCCTTT TTGCTTTCCCCGGGG GGTACAGGTTTGGGG CCCTGTGTCCCTTTT TGCTTTCCCCGGGGG GTACAGGTTTGGGGA CCTGTGTCCCTTTTG GCTTTCCCCGGGGGA TACAGGTTTGGGGAG CTGTGTCCCTTTTGC CTTTCCCCGGGGGAG ACAGGTTTGGGGAGG TGTGTCCCTTTTGCA TTTCCCCGGGGGAGG CAGGTTTGGGGAGGG GTGTCCCTTTTGCAT TTCCCCGGGGGAGGA AGGTTTGGGGAGGGG TGTCCCTTTTGCATA TCCCCGGGGGAGGAA GGTTTGGGGAGGGGG GTCCCTTTTGCATAA CCCCGGGGGAGGAAG GTTTGGGGAGGGGGA TCCCTTTTGCATAAG CCCGGGGGAGGAAGG TTTGGGGAGGGGGAA CCCTTTTGCATAAGA CCGGGGGAGGAAGGG TTGGGGAGGGGGAAG CCTTTTGCATAAGAT CGGGGGAGGAAGGGG TGGGGAGGGGGAAGA CTTTTGCATAAGATT GGGGGAGGAAGGGGG GGGGAGGGGGAAGAG TTTTGCATAAGATTA GGGGAGGAAGGGGGT GGGAGGGGGAAGAGA TTTGCATAAGATTAA GGGAGGAAGGGGGTT GGAGGGGGAAGAGAA TTGCATAAGATTAAA TGCATAAGATTAAAG GCATAAGATTAAAGG CATAAGATTAAAGGA ATAAGATTAAAGGAA TAAGATTAAAGGAAG AAGATTAAAGGAAGG AGATTAAAGGAAGGA GATTAAAGGAAGGAA ATTAAAGGAAGGAAA TTAAAGGAAGGAAAA TAAAGGAAGGAAAAG AAAGGAAGGAAAAGT

EXAMPLE 7

Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: CTCAGCGCCCAGCCG TGGATTCCACAGCTT TACTGTCGCCCCATC TCAGCGCCCAGCCGC GGATTCCACAGCTTC ACTGTCGCCCCATCC CAGCGCCCAGCCGCT GATTCCACAGCTTCG CTGTCGCCCCATCCC AGCGCCCAGCCGCTT ATTCCACAGCTTCGC TGTCGCCCCATCCCT GCGCCCAGCCGCTTC TTCCACAGCTTCGCG GTCGCCCCATCCCTG CGCCCAGCCGCTTCC TCCACAGCTTCGCGC TCGCCCCATCCCTGC GCCCAGCCGCTTCCT CCACAGCTTCGCGCC CGCCCCATCCCTGCG CCCAGCCGCTTCCTG CACAGCTTCGCGCCG GCCCCATCCCTGCGC CCAGCCGCTTCCTGC ACAGCTTCGCGCCGT CCCCATCCCTGCGCG CAGCCGCTTCCTGCC CAGCTTCGCGCCGTG CCCATCCCTGCGCGC AGCCGCTTCCTGCCT AGCTTCGCGCCGTGT CCATCCCTGCGCGCC GCCGCTTCCTGCCTG GCTTCGCGCCGTGTA CATCCCTGCGCGCCC CCGCTTCCTGCCTGG CTTCGCGCCGTGTAC ATCCCTGCGCGCCCA CGCTTCCTGCCTGGA TTCGCGCCGTGTACT TCCCTGCGCGCCCAG GCTTCCTGCCTGGAT TCGCGCCGTGTACTG CCCTGCGCGCCCAGC CTTCCTGCCTGGATT CGCGCCGTGTACTGT CCTGCGCGCCCAGCC TTCCTGCCTGGATTC GCGCCGTGTACTGTC CTGCGCGCCCAGCCT TCCTGCCTGGATTCC CGCCGTGTACTGTCG TGCGCGCCCAGCCTG CCTGCCTGGATTCCA GCCGTGTACTGTCGC GCGCGCCCAGCCTGC CTGCCTGGATTCCAC CCGTGTACTGTCGCC CGCGCCCAGCCTGCC TGCCTGGATTCCACA CGTGTACTGTCGCCC GCGCCCAGCCTGCCA GCCTGGATTCCACAG GTGTACTGTCGCCCC CGCCCAGCCTGCCAA CCTGGATTCCACAGC TGTACTGTCGCCCCA GCCCAGCCTGCCAAG CTGGATTCCACAGCT GTACTGTCGCCCCAT CCCAGCCTGCCAAGC CCAGCCTGCCAAGCA GGGCGCGACCCACGC CTGCTCCGCGGGCCG CAGCCTGCCAAGCAG GGCGCGACCCACGCT TGCTCCGCGGGCCGC AGCCTGCCAAGCAGC GCGCGACCCACGCTC GCTCCGCGGGCCGCC GCCTGCCAAGCAGCG CGCGACCCACGCTCT CTCCGCGGGCCGCCG CCTGCCAAGCAGCGT GCGACCCACGCTCTG TCCGCGGGCCGCCGG CTGCCAAGCAGCGTG CGACCCACGCTCTGG CCGCGGGCCGCCGGT TGCCAAGCAGCGTGC GACCCACGCTCTGGG CGCGGGCCGCCGGTG GCCAAGCAGCGTGCC ACCCACGCTCTGGGC GCGGGCCGCCGGTGG CCAAGCAGCGTGCCC CCCACGCTCTGGGCC CGGGCCGCCGGTGGC CAAGCAGCGTGCCCC CCACGCTCTGGGCCG GGGCCGCCGGTGGCG AAGCAGCGTGCCCCG CACGCTCTGGGCCGC GGCCGCCGGTGGCGC AGCAGCGTGCCCCGG ACGCTCTGGGCCGCT GCCGCCGGTGGCGCG GCAGCGTGCCCCGGT CGCTCTGGGCCGCTG CCGCCGGTGGCGCGG CAGCGTGCCCCGGTT GCTCTGGGCCGCTGC CGCCGGTGGCGCGGG AGCGTGCCCCGGTTG CTCTGGGCCGCTGCG GCCGGTGGCGCGGGC GCGTGCCCCGGTTGC TCTGGGCCGCTGCGC CCGGTGGCGCGGGCT CGTGCCCCGGTTGCA CTGGGCCGCTGCGCT CGGTGGCGCGGGCTG GTGCCCCGGTTGCAG TGGGCCGCTGCGCTG GGTGGCGCGGGCTGG TGCCCCGGTTGCAGG GGGCCGCTGCGCTGA GTGGCGCGGGCTGGC GCCCCGGTTGCAGGC GGCCGCTGCGCTGAC TGGCGCGGGCTGGCG CCCCGGTTGCAGGCG GCCGCTGCGCTGACT GGCGCGGGCTGGCGC CCCGGTTGCAGGCGT CCGCTGCGCTGACTC GCGCGGGCTGGCGCG CCGGTTGCAGGCGTC CGCTGCGCTGACTCT CGCGGGCTGGCGCGA CGGTTGCAGGCGTCA GCTGCGCTGACTCTG GCGGGCTGGCGCGAG GGTTGCAGGCGTCAT CTGCGCTGACTCTGC CGGGCTGGCGCGAGC GTTGCAGGCGTCATG TGCGCTGACTCTGCT GGGCTGGCGCGAGCT TTGCAGGCGTCATGC GCGCTGACTCTGCTG GGCTGGCGCGAGCTC TGCAGGCGTCATGCA CGCTGACTCTGCTGG GCTGGCGCGAGCTCG GCAGGCGTCATGCAG GCTGACTCTGCTGGT CTGGCGCGAGCTCGG CAGGCGTCATGCAGC CTGACTCTGCTGGTG TGGCGCGAGCTCGGG AGGCGTCATGCAGCG TGACTCTGCTGGTGC GGCGCGAGCTCGGGG GGCGTCATGCAGCGG GACTCTGCTGGTGCT GCGCGAGCTCGGGGG GCGTCATGCAGCGGG ACTCTGCTGGTGCTG CGCGAGCTCGGGGGG CGTCATGCAGCGGGC CTCTGCTGGTGCTGC GCGAGCTCGGGGGGC GTCATGCAGCGGGCG TCTGCTGGTGCTGCT CGAGCTCGGGGGGCT TCATGCAGCGGGCGC CTGCTGGTGCTGCTC GAGCTCGGGGGGCTT CATGCAGCGGGCGCG TGCTGGTGCTGCTCC AGCTCGGGGGGCTTG ATGCAGCGGGCGCGA GCTGGTGCTGCTCCG GCTCGGGGGGCTTGG TGCAGCGGGCGCGAC CTGGTGCTGCTCCGC CTCGGGGGGCTTGGG GCAGCGGGCGCGACC TGGTGCTGCTCCGCG TCGGGGGGCTTGGGT CAGCGGGCGCGACCC GGTGCTGCTCCGCGG CGGGGGGCTTGGGTC AGCGGGCGCGACCCA GTGCTGCTCCGCGGG GGGGGGCTTGGGTCC GCGGGCGCGACCCAC TGCTGCTCCGCGGGC GGGGGCTTGGGTCCC CGGGCGCGACCCACG GCTGCTCCGCGGGCC GGGGCTTGGGTCCCG GGGCTTGGGTCCCGT CACTGGCCCAGTGCG GTGCGCGAGCCGGGC GGCTTGGGTCCCGTG ACTGGCCCAGTGCGC TGCGCGAGCCGGGCT GCTTGGGTCCCGTGG CTGGCCCAGTGCGCG GCGCGAGCCGGGCTG CTTGGGTCCCGTGGT TGGCCCAGTGCGCGC CGCGAGCCGGGCTGC TTGGGTCCCGTGGTG GGCCCAGTGCGCGCC GCGAGCCGGGCTGCG TGGGTCCCGTGGTGC GCCCAGTGCGCGCCT CGAGCCGGGCTGCGG GGGTCCCGTGGTGCG CCCAGTGCGCGCCTC GAGCCGGGCTGCGGC GGTCCCGTGGTGCGC CCAGTGCGCGCCTCC AGCCGGGCTGCGGCT GTCCCGTGGTGCGCT CAGTGCGCGCCTCCG GCCGGGCTGCGGCTG TCCCGTGGTGCGCTG AGTGCGCGCCTCCGC CCGGGCTGCGGCTGC CCCGTGGTGCGCTGC GTGCGCGCCTCCGCC CGGGCTGCGGCTGCT CCGTGGTGCGCTGCG TGCGCGCCTCCGCCC GGGCTGCGGCTGCTG CGTGGTGCGCTGCGA GCGCGCCTCCGCCCG GGCTGCGGCTGCTGC GTGGTGCGCTGCGAG CGCGCCTCCGCCCGC GCTGCGGCTGCTGCC TGGTGCGCTGCGAGC GCGCCTCCGCCCGCC CTGCGGCTGCTGCCT GGTGCGCTGCGAGCC CGCCTCCGCCCGCCG TGCGGCTGCTGCCTG GTGCGCTGCGAGCCG GCCTCCGCCCGCCGT GCGGCTGCTGCCTGA TGCGCTGCGAGCCGT CCTCCGCCCGCCGTG CGGCTGCTGCCTGAC GCGCTGCGAGCCGTG CTCCGCCCGCCGTGT GGCTGCTGCCTGACG CGCTGCGAGCCGTGC TCCGCCCGCCGTGTG GCTGCTGCCTGACGT GCTGCGAGCCGTGCG CCGCCCGCCGTGTGC CTGCTGCCTGACGTG CTGCGAGCCGTGCGA CGCCCGCCGTGTGCG TGCTGCCTGACGTGC TGCGAGCCGTGCGAC GCCCGCCGTGTGCGC GCTGCCTGACGTGCG GCGAGCCGTGCGACG CCCGCCGTGTGCGCG CTGCCTGACGTGCGC CGAGCCGTGCGACGC CCGCCGTGTGCGCGG TGCCTGACGTGCGCA GAGCCGTGCGACGCG CGCCGTGTGCGCGGA GCCTGACGTGCGCAC AGCCGTGCGACGCGC GCCGTGTGCGCGGAG CCTGACGTGCGCACT GCCGTGCGACGCGCG CCGTGTGCGCGGAGC CTGACGTGCGCACTG CCGTGCGACGCGCGT CGTGTGCGCGGAGCT TGACGTGCGCACTGA CGTGCGACGCGCGTG GTGTGCGCGGAGCTG GACGTGCGCACTGAG GTGCGACGCGCGTGC TGTGCGCGGAGCTGG ACGTGCGCACTGAGC TGCGACGCGCGTGCA GTGCGCGGAGCTGGT CGTGCGCACTGAGCG GCGACGCGCGTGCAC TGCGCGGAGCTGGTG GTGCGCACTGAGCGA CGACGCGCGTGCACT GCGCGGAGCTGGTGC TGCGCACTGAGCGAG GACGCGCGTGCACTG CGCGGAGCTGGTGCG GCGCACTGAGCGAGG ACGCGCGTGCACTGG GCGGAGCTGGTGCGC CGCACTGAGCGAGGG CGCGCGTGCACTGGC CGGAGCTGGTGCGCG GCACTGAGCGAGGGC GCGCGTGCACTGGCC GGAGCTGGTGCGCGA CACTGAGCGAGGGCC CGCGTGCACTGGCCC GAGCTGGTGCGCGAG ACTGAGCGAGGGCCA GCGTGCACTGGCCCA AGCTGGTGCGCGAGC CTGAGCGAGGGCCAG CGTGCACTGGCCCAG GCTGGTGCGCGAGCC TGAGCGAGGGCCAGC GTGCACTGGCCCAGT CTGGTGCGCGAGCCG GAGCGAGGGCCAGCC TGCACTGGCCCAGTG TGGTGCGCGAGCCGG AGCGAGGGCCAGCCG GCACTGGCCCAGTGC GGTGCGCGAGCCGGG GCGAGGGCCAGCCGT CGAGGGCCAGCCGTG GCCTTCGCTGCCAGC GCGCTGCTGGACGGC GAGGGCCAGCCGTGC CCTTCGCTGCCAGCC CGCTGCTGGACGGCC AGGGCCAGCCGTGCG CTTCGCTGCCAGCCG GCTGCTGGACGGCCG GGGCCAGCCGTGCGG TTCGCTGCCAGCCGT CTGCTGGACGGCCGC GGCCAGCCGTGCGGC TCGCTGCCAGCCGTC TGCTGGACGGCCGCG GCCAGCCGTGCGGCA CGCTGCCAGCCGTCG GCTGGACGGCCGCGG CCAGCCGTGCGGCAT GCTGCCAGCCGTCGC CTGGACGGCCGCGGG CAGCCGTGCGGCATC CTGCCAGCCGTCGCC TGGACGGCCGCGGGC AGCCGTGCGGCATCT TGCCAGCCGTCGCCC GGACGGCCGCGGGCT CCCGTGCGGCATCTA GCCAGCCGTCGCCCG GACGGCCGCGGGCTC CCGTGCGGCATCTAC CCAGCCGTCGCCCGA ACGGCCGCGGGCTCT CGTGCGGCATCTACA CAGCCGTCGCCCGAC CGGCCGCGGGCTCTG GTGCGGCATCTACAC AGCCGTCGCCCGACG GGCCGCGGGCTCTGC TGCGGCATCTACACC GCCGTCGCCCGACGA GCCGCGGGCTCTGCG GCGGCATCTACACCG CCGTCGCCCGACGAG CCGCGGGCTCTGCGT CGGCATCTACACCGA CGTCGCCCGACGAGG CGCGGGCTCTGCGTC GGCATCTACACCGAG GTCGCCCGACGAGGC GCGGGCTCTGCGTCA GCATCTACACCGAGC TCGCCCGACGAGGCG CGGGCTCTGCGTCAA CATCTACACCGAGCG CGCCCGACGAGGCGC GGGCTCTGCGTCAAC ATCTACACCGAGCGC GCCCGACGAGGCGCG GGCTCTGCGTCAACG TCTACACCGAGCGCT CCCGACGAGGCGCGA GCTCTGCGTCAACGC CTACACCGAGCGCTG CCGACGAGGCGCGAC CTCTGCGTCAACGCT TACACCGAGCGCTGT CGACGAGGCGCGACC TCTGCGTCAACGCTA ACACCGAGCGCTGTG GACGAGGCGCGACCG CTGCGTCAACGCTAG CACCGAGCGCTGTGG ACGAGGCGCGACCGC TGCGTCAACGCTAGT ACCGAGCGCTGTGGC CGAGGCGCGACCGCT GCGTCAACGCTAGTG CCGAGCGCTGTGGCT GAGGCGCGACCGCTG CGTCAACGCTAGTGC CGAGCGCTGTGGCTC AGGCGCGACCGCTGC GTCAACGCTAGTGCC GAGCGCTGTGGCTCC GGCGCGACCGCTGCA TCAACGCTAGTGCCG AGCGCTGTGGCTCCG GCGCGACCGCTGCAG CAACGCTAGTGCCGT GCGCTGTGGCTCCGG CGCGACCGCTGCAGG AACGCTAGTGCCGTC CGCTGTGGCTCCGGC GCGACCGCTGCAGGC ACGCTAGTGCCGTCA GCTGTGGCTCCGGCC CGACCGCTGCAGGCG CGCTAGTGCCGTCAG CTGTGGCTCCGGCCT GACCGCTGCAGGCGC GCTAGTGCCGTCAGC TGTGGCTCCGGCCTT ACCGCTGCAGGCGCT CTAGTGCCGTCAGCC GTGGCTCCGGCCTTC CCGCTGCAGGCGCTG TAGTGCCGTCAGCCG TGGCTCCGGCCTTCG CGCTGCAGGCGCTGC AGTGCCGTCAGCCGC GGCTCCGGCCTTCGC GCTGCAGGCGCTGCT GTGCCGTCAGCCGCC GCTCCGGCCTTCGCT CTGCAGGCGCTGCTG TGCCGTCAGCCGCCT CTCCGGCCTTCGCTG TGCAGGCGCTGCTGG GCCGTCAGCCGCCTG TCCGGCCTTCGCTGC GCAGGCGCTGCTGGA CCGTCAGCCGCCTGC CCGGCCTTCGCTGCC CAGGCGCTGCTGGAC CGTCAGCCGCCTGCG CGGCCTTCGCTGCCA AGGCGCTGCTGGACG GTCAGCCGCCTGCGC GGCCTTCGCTGCCAG GGCGCTGCTGGACGG TCAGCCGCCTGCGCG CAGCCGCCTGCGCGC GAAATGCTAGTGAGT GAGAGCCCGTCCGTC AGCCGCCTGCGCGCC AAATGCTAGTGAGTC AGAGCCCGTCCGTCT GCCGCCTGCGCGCCT AATGCTAGTGAGTCG GAGCCCGTCCGTCTC CCGCCTGCGCGCCTA ATGCTAGTGAGTCGG AGCCCGTCCGTCTCC CGCCTGCGCGCCTAC TGCTAGTGAGTCGGA GCCCGTCCGTCTCCA GCCTGCGCGCCTACC GCTAGTGAGTCGGAG CCCGTCCGTCTCCAG CCTGCGCGCCTACCT CTAGTGAGTCGGAGG CCGTCCGTCTCCAGC CTGCGCGCCTACCTG TAGTGAGTCGGAGGA CGTCCGTCTCCAGCA TGCGCGCCTACCTGC AGTGAGTCGGAGGAA GTCCGTCTCCAGCAC GCGCGCCTACCTGCT GTGAGTCGGAGGAAG TCCGTCTCCAGCACG CGCGCCTACCTGCTG TGAGTCGGAGGAAGA CCGTCTCCAGCACGC GCGCCTACCTGCTGC GAGTCGGAGGAAGAC CGTCTCCAGCACGCA CGCCTACCTGCTGCC AGTCGGAGGAAGACC GTCTCCAGCACGCAC GCCTACCTGCTGCCA GTCGGAGGAAGACCG TCTCCAGCACGCACC CCTACCTGCTGCCAG TCGGAGGAAGACCGC CTCCAGCACGCACCG CTACCTGCTGCCAGC CGGAGGAAGACCGCA TCCAGCACGCACCGG TACCTGCTGCCAGCG GGAGGAAGACCGCAG CCAGCACGCACCGGG ACCTGCTGCCAGCGC GAGGAAGACCGCAGC CAGCACGCACCGGGT CCTGCTGCCAGCGCC AGGAAGACCGCAGCG AGCACGCACCGGGTG CTGCTGCCAGCGCCG GGAAGACCGCAGCGC GCACGCACCGGGTGT TGCTGCCAGCGCCGC GAAGACCGCAGCGCC CACGCACCGGGTGTC GCTGCCAGCGCCGCC AAGACCGCAGCGCCG ACGCACCGGGTGTCT CTGCCAGCGCCGCCA AGACCGCAGCGCCGG CGCACCGGGTGTCTG TGCCAGCGCCGCCAG GACCGCAGCGCCGGC GCACCGGGTGTCTGA GCCAGCGCCGCCAGC ACCGCAGCGCCGGCA CACCGGGTGTCTGAT CCAGCGCCGCCAGCT CCGCAGCGCCGGCAG ACCGGGTGTCTGATC CAGCGCCGCCAGCTC CGCAGCGCCGGCAGT CCGGGTGTCTGATCC AGCGCCGCCAGCTCC GCAGCGCCGGCAGTG CGGGTGTCTGATCCC GCGCCGCCAGCTCCA CAGCGCCGGCAGTGT GGGTGTCTGATCCCA CGCCGCCAGCTCCAG AGCGCCGGCAGTGTG GGTGTCTGATCCCAA GCCGCCAGCTCCAGG GCGCCGGCAGTGTGG GTGTCTGATCCCAAG CCGCCAGCTCCAGGA CGCCGGCAGTGTGGA TGTCTGATCCCAAGT CGCCAGCTCCAGGAA GCCGGCAGTGTGGAG GTCTGATCCCAAGTT GCCAGCTCCAGGAAA CCGGCAGTGTGGAGA TCTGATCCCAAGTTC CCAGCTCCAGGAAAT CGGCAGTGTGGAGAG CTGATCCCAAGTTCC CAGCTCCAGGAAATG GGCAGTGTGGAGAGC TGATCCCAAGTTCCA AGCTCCAGGAAATGC GCAGTGTGGAGAGCC GATCCCAAGTTCCAC GCTCCAGGAAATGCT CAGTGTGGAGAGCCC ATCCCAAGTTCCACC CTCCAGGAAATGCTA AGTGTGGAGAGCCCG TCCCAAGTTCCACCC TCCAGGAAATGCTAG GTGTGGAGAGCCCGT CCCAAGTTCCACCCC CCAGGAAATGCTAGT TGTGGAGAGCCCGTC CCAAGTTCCACCCCC CAGGAAATGCTAGTG GTGGAGAGCCCGTCC CAAGTTCCACCCCCT AGGAAATGCTAGTGA TGGAGAGCCCGTCCG AAGTTCCACCCCCTC GGAAATGCTAGTGAG GGAGAGCCCGTCCGT AGTTCCACCCCCTCC GTTCCACCCCCTCCA ATGCTAAAGACAGCC AGCACAGATACCCAG TTCCACCCCCTCCAT TGCTAAAGACAGCCA GCACAGATACCCAGA TCCACCCCCTCCATT GCTAAAGACAGCCAG CACAGATACCCAGAA CCACCCCCTCCATTC CTAAAGACAGCCAGC ACAGATACCCAGAAC CACCCCCTCCATTCA TAAAGACAGCCAGCG CAGATACCCAGAACT ACCCCCTCCATTCAA AAAGACAGCCAGCGC AGATACCCAGAACTT CCCCCTCCATTCAAA AAGACAGCCAGCGCT GATACCCAGAACTTC CCCCTCCATTCAAAG AGACAGCCAGCGCTA ATACCCAGAACTTCT CCCTCCATTCAAAGA GACAGCCAGCGCTAC TACCCAGAACTTCTC CCTCCATTCAAAGAT ACAGCCAGCGCTACA ACCCAGAACTTCTCC CTCCATTCAAAGATA CAGCCAGCGCTACAA CCCAGAACTTCTCCT TCCATTCAAAGATAA AGCCAGCGCTACAAA CCAGAACTTCTCCTC CCATTCAAAGATAAT GCCAGCGCTACAAAG CAGAACTTCTCCTCC CATTCAAAGATAATC CCAGCGCTACAAAGT AGAACTTCTCCTCCG ATTCAAAGATAATCA CAGCGCTACAAAGTT GAACTTCTCCTCCGA TTCAAAGATAATCAT AGCGCTACAAAGTTG AACTTCTCCTCCGAG TCAAAGATAATCATC GCGCTACAAAGTTGA ACTTCTCCTCCGAGT CAAAGATAATCATCA CGCTACAAAGTTGAC CTTCTCCTCCGAGTC AAAGATAATCATCAT GCTACAAAGTTGACT TTCTCCTCCGAGTCC AAGATAATCATCATC CTACAAAGTTGACTA TCTCCTCCGAGTCCA AGATAATCATCATCA TACAAAGTTGACTAC CTCCTCCGAGTCCAA GATAATCATCATCAA ACAAAGTTGACTACG TCCTCCGAGTCCAAG ATAATCATCATCAAG CAAAGTTGACTACGA CCTCCGAGTCCAAGC TAATCATCATCAAGA AAAGTTGACTACGAG CTCCGAGTCCAAGCG AATCATCATCAAGAA AAGTTGACTACGAGT TCCGAGTCCAAGCGG ATCATCATCAAGAAA AGTTGACTACGAGTC CCGAGTCCAAGCGGG TCATCATCAAGAAAG GTTGACTACGAGTCT CGAGTCCAAGCGGGA CATCATCAAGAAAGG TTGACTACGAGTCTC GAGTCCAAGCGGGAG ATCATCAAGAAAGGG TGACTACGAGTCTCA AGTCCAAGCGGGAGA TCATCAAGAAAGGGC GACTACGAGTCTCAG GTCCAAGCGGGAGAC CATCAAGAAAGGGCA ACTACGAGTCTCAGA TCCAAGCGGGAGACA ATCAAGAAAGGGCAT CTACGAGTCTCAGAG CCAAGCGGGAGACAG TCAAGAAAGGGCATG TACGAGTCTCAGAGC CAAGCGGGAGACAGA CAAGAAAGGGCATGC ACGAGTCTCAGAGCA AAGCGGGAGACAGAA AAGAAAGGGCATGCT CGAGTCTCAGAGCAC AGCGGGAGACAGAAT AGAAAGGGCATGCTA GAGTCTCAGAGCACA GCGGGAGACAGAATA GAAAGGGCATGCTAA AGTCTCAGAGCACAG CGGGAGACAGAATAT AAAGGGCATGCTAAA GTCTCAGAGCACAGA GGGAGACAGAATATG AAGGGCATGCTAAAG TCTCAGAGCACAGAT GGAGACAGAATATGG AGGGCATGCTAAAGA CTCAGAGCACAGATA GAGACAGAATATGGT GGGCATGCTAAAGAC TCAGAGCACAGATAC AGACAGAATATGGTC GGCATGCTAAAGACA CAGAGCACAGATACC GACAGAATATGGTCC GCATGCTAAAGACAG AGAGCACAGATACCC ACAGAATATGGTCCC CATGCTAAAGACAGC GAGCACAGATACCCA CAGAATATGGTCCCT AGAATATGGTCCCTG ACCTGAAGTTCCTCA CCCAACTGTGACAAG GAATATGGTCCCTGC CCTGAAGTTCCTCAA CCAACTGTGACAAGA AATATGGTCCCTGCC CTGAAGTTCCTCAAT CAACTGTGACAAGAA ATATGGTCCCTGCCG TGAAGTTCCTCAATG AACTGTGACAAGAAC TATGGTCCCTGCCGT GAAGTTCCTCAATGT ACTGTGACAAGAAGG ATGGTCCCTGCCGTA AAGTTCCTCAATGTG CTGTGACAAGAAGGG TGGTCCCTGCCGTAG AGTTCCTCAATGTGC TGTGACAAGAAGGGA GGTCCCTGCCGTAGA GTTCCTCAATGTGCT GTGACAAGAAGGGAT GTCCCTGCCGTAGAG TTCCTCAATGTGCTG TGACAAGAAGGGATT TCCCTGCCGTAGAGA TCCTCAATGTGCTGA GACAAGAAGGGATTT CCCTGCCGTAGAGAA CCTCAATGTGCTGAG ACAAGAAGGGATTTT CCTGCCGTAGAGAAA CTCAATGTGCTGAGT CAAGAAGGGATTTTA CTGCCGTAGAGAAAT TCAATGTGCTGAGTC AAGAAGGGATTTTAT TGCCGTAGAGAAATG CAATGTGCTGAGTCC AGPAGGGATTTTATA GCCGTAGAGAAATGG AATGTGCTGAGTCCC GAAGGGATTTTATAA CCGTAGAGAAATGGA ATGTGCTGAGTCCCA AAGGGATTTTATAAG CGTAGAGAAATGGAA TGTGCTGAGTCCCAG AGGGATTTTATAAGA GTAGAGAAATGGAAG GTGCTGAGTCCCAGG GGGATTTTATAAGAA TAGAGAAATGGAAGA TGCTGAGTCCCAGGG GGATTTTATAAGAAA AGAGAAATGGAAGAC GCTGAGTCCCAGGGG GATTTTATAAGAAAA GAGAAATGGAAGACA CTGAGTCCCAGGGGT ATTTTATAAGAAAAA AGAAATGGAAGACAC TGAGTCCCAGGGGTG TTTTATAAGAAAAAG GAAATGGAAGACACA GAGTCCCAGGGGTGT TTTATAAGAAAAAGC AAATGGAAGACACAC AGTCCCAGGGGTGTA TTATAAGAAAAAGCA AATGGAAGACACACT GTCCCAGGGGTGTAC TATAAGAAAAAGCAG ATGGAAGACACACTG TCCCAGGGGTGTACA ATAAGAAAAAGCAGT TGGAAGACACACTGA CCCAGGGGTGTACAC TAAGAAAAAGCAGTG GGAAGACACACTGAA CCAGGGGTGTACACA AAGAAAAAGCAGTGT GAAGACACACTGAAT CAGGGGTGTACACAT AGAAAAAGCAGTGTC AAGACACACTGAATC AGGGGTGTACACATT GAAAAAGCAGTGTCG AGACACACTGAATCA GGGGTGTACACATTC AAAAAGCAGTGTCGC GACACACTGAATCAC GGGTGTACACATTCC AAAAGCAGTGTCGCC ACACACTGAATCACC GGTGTACACATTCCC AAAGCAGTGTCGCCC CACACTGAATCACCT GTGTACACATTCCCA AAGCAGTGTCGCCCT ACACTGAATCACCTG TGTACACATTCCCAA AGCAGTGTCGCCCTT CACTGAATCACCTGA GTACACATTCCCAAC GCAGTGTCGCCCTTC ACTGAATCACCTGAA TACACATTCCCAACT CAGTGTCGCCCTTCC CTGAATCACCTGAAG ACACATTCCCAACTG AGTGTCGCCCTTCCA TGAATCACCTGAAGT CACATTCCCAACTGT GTGTCGCCCTTCCAA GAATCACCTGAAGTT ACATTCCCAACTGTG TGTCGCCCTTCCAAA AATCACCTGAAGTTC CATTCCCAACTGTGA GTCGCCCTTCCAAAG ATCACCTGAAGTTCC ATTCCCAACTGTGAC TCGCCCTTCCAAAGG TCACCTGAAGTTCCT TTCCCAACTGTGACA CGCCCTTCCAAAGGC CACCTGAAGTTCCTC TCCCAACTGTGACAA GCCCTTCCAAAGGCA CCCTTCCAAAGGCAG AGTATGGGCAGCCTC GACGTGCACTGCTAC CCTTCCAAAGGCAGG GTATGGGCAGCCTCT ACGTGCACTGCTACA CTTCCAAAGGCAGGA TATGGGCAGCCTCTC CGTGCACTGCTACAG TTCCAAAGGCAGGAA ATGGGCAGCCTCTCC GTGCACTGCTACAGC TCCAAAGGCAGGAAG TGGGCAGCCTCTCCC TGCACTGCTACAGCA CCAAAGGCAGGAAGC GGGCAGCCTCTCCCA GCACTGCTACAGCAT CAAAGGCAGGAAGCG GGCAGCCTCTCCCAG CACTGCTACAGCATG AAAGGCAGGAAGCGG GCAGCCTCTCCCAGG ACTGCTACAGCATGC AAGGCAGGAAGCGGG CAGCCTCTCCCAGGC CTGCTACAGCATGCA AGGCAGGAAGCGGGG AGCCTCTCCCAGGCT TGCTACAGCATGCAG GGCAGGAAGCGGGGC GCCTCTCCCAGGCTA GCTACAGCATGCAGA GCAGGAAGCGGGGCT CCTCTCCCAGGCTAC CTACAGCATGCAGAG CAGGAAGCGGGGCTT CTCTCCCAGGCTACA TACAGCATGCAGAGC AGGAAGCGGGGCTTC TCTCCCAGGCTACAC ACAGCATGCAGAGCA GGAAGCGGGGCTTCT CTCCCAGGCTACACC CAGCATGCAGAGCAA GAAGCGGGGCTTCTG TCCCAGGCTACACCA AGCATGCAGAGCAAG AAGCGGGGCTTCTGC CCCAGGCTACACCAC GCATGCAGAGCAAGT AGCGGGGCTTCTGCT CCAGGCTACACCACC CATGCAGAGCAAGTA GCGGGGCTTCTGCTG CAGGCTACACCACCA ATGCAGAGCAAGTAG CGGGGCTTCTGCTGG AGGCTACACCACCAA TGCAGAGCAAGTAGA GGGGCTTCTGCTGGT GGCTACACCACCAAG GCAGAGCAAGTAGAC GGGCTTCTGCTGGTG GCTACACCACCAAGG CAGAGCAAGTAGACG GGCTTCTGCTGGTGT CTACACCACCAAGGG AGAGCAAGTAGACGC GCTTCTGCTGGTGTG TACACCACCAAGGGG GAGCAAGTAGACGCC CTTCTGCTGGTGTGT ACACCACCAAGGGGA AGCAAGTAGACGCCT TTCTGCTGGTGTGTG CACCACCAAGGGGAA GCAAGTAGACGCCTG TCTGCTGGTGTGTGG ACCACCAAGGGGAAG CAAGTAGACGCCTGC CTGCTGGTGTGTGGA CCACCAAGGGGAAGG AAGTAGACGCCTGCC TGCTGGTGTGTGGAT CACCAAGGGGAAGGA AGTAGACGCCTGCCG GCTGGTGTGTGGATA ACCAAGGGGAAGGAG GTAGACGCCTGCCGC CTGGTGTGTGGATAA CCAAGGGGAAGGAGG TAGACGCCTGCCGCA TGGTGTGTGGATAAG CAAGGGGAAGGAGGA AGACGCCTGCCGCAA GGTGTGTGGATAAGT AAGGGGAAGGAGGAC GACGCCTGCCGCAAG GTGTGTGGATAAGTA AGGGGAAGGAGGACG ACGCCTGCCGCAAGT TGTGTGGATAAGTAT GGGGAAGGAGGACGT CGCCTGCCGCAAGTT GTGTGGATAAGTATG GGGAAGGAGGACGTG GCCTGCCGCAAGTTA TGTGGATAAGTATGG GGAAGGAGGACGTGC CCTGCCGCAAGTTAA GTGGATAAGTATGGG GAAGGAGGACGTGCA CTGCCGCAAGTTAAT TGGATAAGTATGGGC AAGGAGGACGTGCAC TGCCGCAAGTTAATG GGATAAGTATGGGCA AGGAGGACGTGCACT GCCGCAAGTTAATGT GATAAGTATGGGCAG GGAGGACGTGCACTG CCGCAAGTTAATGTG ATAAGTATGGGCAGC GAGGACGTGCACTGC CGCAAGTTAATGTGG TAAGTATGGGCAGCC AGGACGTGCACTGCT GCAAGTTAATGTGGA AAGTATGGGCAGCCT GGACGTGCACTGCTA CAAGTTAATGTGGAG AAGTTAATGTGGAGC TGCCAAGGACATGAC TTCTGTTTGTGGTGA AGTTAATGTGGAGCT GCCAAGGACATGACC TCTGTTTGTGGTGAA GTTAATGTGGAGCTC CCAAGGACATGACCA CTGTTTGTGGTGAAC TTAATGTGGAGCTCA CAAGGACATGACCAG TGTTTGTGGTGAACT TAATGTGGAGCTCAA AAGGACATGACCAGC GTTTGTGGTGAACTG AATGTGGAGCTCAAA AGGACATGACCAGCA TTTGTGGTGAACTGA ATGTGGAGCTCAAAT GGACATGACCAGCAG TTGTGGTGAACTGAT TGTGGAGCTCAAATA GACATGACCAGCAGC TGTGGTGAACTGATT GTGGAGCTCAAATAT ACATGACCAGCAGCT GTGGTGAACTGATTT TGGAGCTCAAATATG CATGACCAGCAGCTG TGGTGAACTGATTTT GGAGCTCAAATATGC ATGACCAGCAGCTGG GGTGAACTGATTTTT GAGCTCAAATATGCC TGACCAGCAGCTGGC GTGAACTGATTTTTT AGCTCAAATATGCCT GACCAGCAGCTGGCT TGAACTGATTTTTTT GCTCAAATATGCCTT ACCAGCAGCTGGCTA GAACTGATTTTTTTT CTCAAATATGCCTTA CCAGCAGCTGGCTAC AACTGATTTTTTTTA TCAAATATGCCTTAT CAGCAGCTGGCTACA ACTGATTTTTTTTAA CAAATATGCCTTATT AGCAGCTGGCTACAG CTGATTTTTTTTAAA AAATATGCCTTATTT GCAGCTGGCTACAGC TGATTTTTTTTAAAC AATATGCCTTATTTT CAGCTGGCTACAGCC GATTTTTTTTAAACC ATATGCCTTATTTTG AGCTGGCTACAGCCT ATTTTTTTTAAACCA TATGCCTTATTTTGC GCTGGCTACAGCCTC TTTTTTTTAAACCAA ATGCCTTATTTTGCA CTGGCTACAGCCTCG TTTTTTTAAACCAAA TGCCTTATTTTGCAC TGGCTACAGCCTCGA TTTTTTAAACCAAAG GCCTTATTTTGCACA GGCTACAGCCTCGAT TTTTTAAACCAAAGT CCTTATTTTGCACAA GCTACAGCCTCGATT TTTTAAACCAAAGTT CTTATTTTGCACAAA CTACAGCCTCGATTT TTTAAACCAAAGTTT TTATTTTGCACAAAA TACAGCCTCGATTTA TTAAACCAAAGTTTA TATTTTGCACAAAAG ACAGCCTCGATTTAT TAAACCAAAGTTTAG ATTTTGCACAAAAGA CAGCCTCGATTTATA AAACCAAAGTTTAGA TTTTGCACAAAAGAC AGCCTCGATTTATAT AACCAAAGTTTAGAA TTTGCACAAAAGACT GCCTCGATTTATATT ACCAAAGTTTAGAAA TTGCACAAAAGACTG CCTCGATTTATATTT CCAAAGTTTAGAAAG TGCACAAAAGACTGC CTCGATTTATATTTC CAAAGTTTAGAAAGA GCACAAAAGACTGCC TCGATTTATATTTCT AAAGTTTAGAAAGAG CACAAAAGACTGCCA CGATTTATATTTCTG AAGTTTAGAAAGAGG ACAAAAGACTGCCAA GATTTATATTTCTGT AGTTTAGAAAGAGGT CAAAAGACTGCCAAG ATTTATATTTCTGTT GTTTAGAAAGAGGTT AAAAGACTGCCAAGG TTTATATTTCTGTTT TTTAGAAAGAGGTTT AAAGACTGCCAAGGA TTATATTTCTGTTTG TTAGAAAGAGGTTTT AAGACTGCCAAGGAC TATATTTCTGTTTGT TAGAAAGAGGTTTTT AGACTGCCAAGGACA ATATTTCTGTTTGTG AGAAAGAGGTTTTTG GACTGCCAAGGACAT TATTTCTGTTTGTGG GAAAGAGGTTTTTGA ACTGCCAAGGACATG ATTTCTGTTTGTGGT AAAGAGGTTTTTGAA CTGCCAAGGACATGA TTTCTGTTTGTGGTG AAGAGGTTTTTGAAA AGAGGTTTTTGAAAT AGCATCTTTTCACTT TTTCTTGTCGCTTCC GAGGTTTTTGAAATG GCATCTTTTCACTTT TTCTTGTCGCTTCCT AGGTTTTTGAAATGC CATCTTTTCACTTTC TCTTGTCGCTTCCTA GGTTTTTGAAATGCC ATCTTTTCACTTTCC CTTGTCGCTTCCTAT GTTTTTGAAATGCCT TCTTTTCACTTTCCA TTGTCGCTTCCTATC TTTTTGAAATGCCTA CTTTTCACTTTCCAG TGTCGCTTCCTATCA TTTTGAAATGCCTAT TTTTCACTTTCCAGT GTCGCTTCCTATCAA TTTGAAATGCCTATG TTTCACTTTCCAGTA TCGCTTCCTATCAAA TTGAAATGCCTATGG TTCACTTTCCAGTAG CGCTTCCTATCAAAA TGAAATGCCTATGGT TCACTTTCCAGTAGT GCTTCCTATCAAAAT GAAATGCCTATGGTT CACTTTCCAGTAGTC CTTCCTATCAAAATA AAATGCCTATGGTTT ACTTTCCAGTAGTCA TTCCTATCAAAATAT AATGCCTATGGTTTC CTTTCCAGTAGTCAG TCCTATCAAAATATT ATGCCTATGGTTTCT TTTCCAGTAGTCAGC CCTATCAAAATATTC TGCCTATGGTTTCTT TTCCAGTAGTCAGCA CTATCAAAATATTCA GCCTATGGTTTCTTT TCCAGTAGTCAGCAA TATCAAAATATTCAG CCTATGGTTTCTTTG CCAGTAGTCAGCAAA ATCAAAATATTCAGA CTATGGTTTCTTTGA CAGTAGTCAGCAAAG TCAAAATATTCAGAG TATGGTTTCTTTGAA AGTAGTCAGCAAAGA CAAAATATTCAGAGA ATGGTTTCTTTGAAT GTAGTCAGCAAAGAG AAAATATTCAGAGAC TGGTTTCTTTGAATG TAGTCAGCAAAGAGC AAATATTCAGAGACT GGTTTCTTTGAATGG AGTCAGCAAAGAGCA AATATTCAGAGACTC GTTTCTTTGAATGGT GTCAGCAAAGAGCAG ATATTCAGAGACTCG TTTCTTTGAATGGTA TCAGCAAAGAGCAGT TATTCAGAGACTCGA TTCTTTGAATGGTAA CAGCAAAGAGCAGTT ATTCAGAGACTCGAG TCTTTGAATGGTAAA AGCAAAGAGCAGTTT TTCAGAGACTCGAGC CTTTGAATGGTAAAC GCAAAGAGCAGTTTG TCAGAGACTCGAGCA TTTGAATGGTAAACT CAAAGAGCAGTTTGA CAGAGACTCGAGCAC TTGAATGGTAAACTT AAAGAGCAGTTTGAA AGAGACTCGAGCACA TGAATGGTAAACTTG AAGAGCAGTTTGAAT GAGACTCGAGCACAG GAATGGTAAACTTGA AGAGCAGTTTGAATT AGACTCGAGCACAGC AATGGTAAACTTGAG GAGCAGTTTGAATTT GACTCGAGCACAGCA ATGGTAAACTTGAGC AGCAGTTTGAATTTT ACTCGAGCACAGCAC TGGTAAACTTGAGCA GCAGTTTGAATTTTC CTCGAGCACAGCACC GGTAAACTTGAGCAT CAGTTTGAATTTTCT TCGAGCACAGCACCC GTAAACTTGAGCATC AGTTTGAATTTTCTT CGAGCACAGCACCCA TAAACTTGAGCATCT GTTTGAATTTTCTTG GAGCACAGCACCCAG AAACTTGAGCATCTT TTTGAATTTTCTTGT AGCACAGCACCCAGA AACTTGAGCATCTTT TTGAATTTTCTTGTC GCACAGCACCCAGAC ACTTGAGCATCTTTT TGAATTTTCTTGTCG CACAGCACCCAGACT CTTGAGCATCTTTTC GAATTTTCTTGTCGC ACAGCACCCAGACTT TTGAGCATCTTTTCA AATTTTCTTGTCGCT CAGCACCCAGACTTC TGAGCATCTTTTCAC ATTTTCTTGTCGCTT AGCACCCAGACTTCA GAGCATCTTTTCACT TTTTCTTGTCGCTTC GCACCCAGACTTCAT CACCCAGACTTCATG CGAAGCGGCCGACCA CCTATGTAGAGAACA ACCCAGACTTCATGC GAAGCGGCCGACCAC CTATGTAGAGAACAC CCCAGACTTCATGCG AAGCGGCCGACCACT TATGTAGAGAACACG CCAGACTTCATGCGC AGCGGCCGACCACTG ATGTAGAGAACACGC CAGACTTCATGCGCC GCGGCCGACCACTGA TGTAGAGAACACGCT AGACTTCATGCGCCC CGGCCGACCACTGAC GTAGAGAACACGCTT GACTTCATGCGCCCG GGCCGACCACTGACT TAGAGAACACGCTTC ACTTCATGCGCCCGT GCCGACCACTGACTT AGAGAACACGCTTCA CTTCATGCGCCCGTG CCGACCACTGACTTT GAGAACACGCTTCAC TTCATGCGCCCGTGG CGACCACTGACTTTG AGAACACGCTTCACC TCATGCGCCCGTGGA GACCACTGACTTTGT GAACACGCTTCACCC CATGCGCCCGTGGAA ACCACTGACTTTGTG AACACGCTTCACCCC ATGCGCCCGTGGAAT CCACTGACTTTGTGA ACACGCTTCACCCCC TGCGCCCGTGGAATG CACTGACTTTGTGAC CACGCTTCACCCCCA GCGCCCGTGGAATGC ACTGACTTTGTGACT ACGCTTCACCCCCAC CGCCCGTGGAATGCT CTGACTTTGTGACTT CGCTTCACCCCCACT GCCCGTGGAATGCTC TGACTTTGTGACTTA GCTTCACCCCCACTC CCCGTGGAATGCTCA GACTTTGTGACTTAG CTTCACCCCCACTCC CCGTGGAATGCTCAC ACTTTGTGACTTAGG TTCACCCCCACTCCC CGTGGAATGCTCACC CTTTGTGACTTAGGC TCACCCCCACTCCCC GTGGAATGCTCACCA TTTGTGACTTAGGCG CACCCCCACTCCCCG TGGAATGCTCACCAC TTGTGACTTAGGCGG ACCCCCACTCCCCGT GGAATGCTCACCACA TGTGACTTAGGCGGC CCCCCACTCCCCGTA GAATGCTCACCACAT GTGACTTAGGCGGCT CCCCACTCCCCGTAC AATGCTCACCACATG TGACTTAGGCGGCTG CCCACTCCCCGTACA ATGCTCACCACATGT GACTTAGGCGGCTGT CCACTCCCCGTACAG TGCTCACCACATGTT ACTTAGGCGGCTGTG CACTCCCCGTACAGT GCTCACCACATGTTG CTTAGGCGGCTGTGT ACTCCCCGTACAGTG CTCACCACATGTTGG TTAGGCGGCTGTGTT CTCCCCGTACAGTGC TCACCACATGTTGGT TAGGCGGCTGTGTTG TCCCCGTACAGTGCG CACCACATGTTGGTC AGGCGGCTGTGTTGC CCCCGTACAGTGCGC ACCACATGTTGGTCG GGCGGCTGTGTTGCC CCCGTACAGTGCGCA CCACATGTTGGTCGA GCGGCTGTGTTGCCT CCGTACAGTGCGCAC CACATGTTGGTCGAA CGGCTGTGTTGCCTA CGTACAGTGCGCACA ACATGTTGGTCGAAG GGCTGTGTTGCCTAT GTACAGTGCGCACAG CATGTTGGTCGAAGC GCTGTGTTGCCTATG TACAGTGCGCACAGG ATGTTGGTCGAAGCG CTGTGTTGCCTATGT ACAGTGCGCACAGGC TGTTGGTCGAAGCGG TGTGTTGCCTATGTA CAGTGCGCACAGGCT GTTGGTCGAAGCGGC GTGTTGCCTATGTAG AGTGCGCACAGGCTT TTGGTCGAAGCGGCC TGTTGCCTATGTAGA GTGCGCACAGGCTTT TGGTCGAAGCGGCCG GTTGCCTATGTAGAG TGCGCACAGGCTTTA GGTCGAAGCGGCCGA TTGCCTATGTAGAGA GCGCACAGGCTTTAT GTCGAAGCGGCCGAC TGCCTATGTAGAGAA CGCACAGGCTTTATC TCGAAGCGGCCGACC GCCTATGTAGAGAAC GCACAGGCTTTATCG CACAGGCTTTATCGA CCGGACATCCCAACG GTGTCATTTCTGAAA ACAGGCTTTATCGAG CGGACATCCCAACGC TGTCATTTCTGAAAC CAGGCTTTATCGAGA GGACATCCCAACGCA GTCATTTCTGAAACA AGGCTTTATCGAGAA GACATCCCAACGCAT TCATTTCTGAAACAA GGCTTTATCGAGAAT ACATCCCAACGCATG CATTTCTGAAACAAG GCTTTATCGAGAATA CATCCCAACGCATGC ATTTCTGAAACAAGG CTTTATCGAGAATAG ATCCCAACGCATGCT TTTCTGAAACAAGGG TTTATCGAGAATAGG TCCCAACGCATGCTC TTCTGAAACAAGGGC TTATCGAGAATAGGA CCCAACGCATGCTCC TCTGAAACAAGGGCG TATCGAGAATAGGAA CCAACGCATGCTCCT CTGAAACAAGGGCGT ATCGAGAATAGGAAA CAACGCATGCTCCTG TGAAACAAGGGCGTG TCGAGAATAGGAAAA AACGCATGCTCCTGG GAAACAAGGGCGTGG CGAGAATAGGAAAAC ACGCATGCTCCTGGA AAACAAGGGCGTGGA GAGAATAGGAAAACC CGCATGCTCCTGGAG AACAAGGGCGTGGAT AGAATAGGAAAACCT GCATGCTCCTGGAGC ACAAGGGCGTGGATC GAATAGGAAAACCTT CATGCTCCTGGAGCT CAAGGGCGTGGATCC AATAGGAAAACCTTT ATGCTCCTGGAGCTC AAGGGCGTGGATCCC ATAGGAAAACCTTTA TGCTCCTGGAGCTCA AGGGCGTGGATCCCT TAGGAAAACCTTTAA GCTCCTGGAGCTCAC GGGCGTGGATCCCTC AGGAAAACCTTTAAA CTCCTGGAGCTCACA GGCGTGGATCCCTCA GGAAAACCTTTAAAC TCCTGGAGCTCACAG GCGTGGATCCCTCAA GAAAACCTTTAAACC CCTGGAGCTCACAGC CGTGGATCCCTCAAC AAAACCTTTAAACCC CTGGAGCTCACAGCC GTGGATCCCTCAACC AAACCTTTAAACCCC TGGAGCTCACAGCCT TGGATCCCTCAACCA AACCTTTAAACCCCG GGAGCTCACAGCCTT GGATCCCTCAACCAA ACCTTTAAACCCCGG GAGCTCACAGCCTTC GATCCCTCAACCAAG CCTTTAAACCCCGGT AGCTCACAGCCTTCT ATCCCTCAACCAAGA CTTTAAACCCCGGTC GCTCACAGCCTTCTG TCCCTCAACCAAGAA TTTAAACCCCGGTCA CTCACAGCCTTCTGT CCCTCAACCAAGAAG TTAAACCCCGGTCAT TCACAGCCTTCTGTG CCTCAACCAAGAAGA TAAACCCCGGTCATC CACAGCCTTCTGTGG CTCAACCAAGAAGAA AAACCCCGGTCATCC ACAGCCTTCTGTGGT TCAACCAAGAAGAAT AACCCCGGTCATCCG CAGCCTTCTGTGGTG CAACCAAGAAGAATG ACCCCGGTCATCCGG AGCCTTCTGTGGTGT AACCAAGAAGAATGT CCCCGGTCATCCGGA GCCTTCTGTGGTGTC ACCAAGAAGAATGTT CCCGGTCATCCGGAC CCTTCTGTGGTGTCA CCAAGAAGAATGTTT CCGGTCATCCGGACA CTTCTGTGGTGTCAT CAAGAAGAATGTTTA CGGTCATCCGGACAT TTCTGTGGTGTCATT AAGAAGAATGTTTAT GGTCATCCGGACATC TCTGTGGTGTCATTT AGAAGAATGTTTATG GTCATCCGGACATCC CTGTGGTGTCATTTC GAAGAATGTTTATGT TCATCCGGACATCCC TGTGGTGTCATTTCT AAGAATGTTTATGTC CATCCGGACATCCCA GTGGTGTCATTTCTG AGAATGTTTATGTCT ATCCGGACATCCCAA TGGTGTCATTTCTGA GAATGTTTATGTCTT TCCGGACATCCCAAC GGTGTCATTTCTGAA AATGTTTATGTCTTC ATGTTTATGTCTTCA AGAAAATAAGGTGGA AGAATGTTCTAGGGC TGTTTATGTCTTCAA GAAAATAAGGTGGAG GAATGTTCTAGGGCA GTTTATGTCTTCAAG AAAATAAGGTGGAGT AATGTTCTAGGGCAC TTTATGTCTTCAAGT AAATAAGGTGGAGTC ATGTTCTAGGGCACT TTATGTCTTCAAGTG AATAAGGTGGAGTCC TGTTCTAGGGCACTC TATGTCTTCAAGTGA ATAAGGTGGAGTCCT GTTCTAGGGCACTCT ATGTCTTCAAGTGAC TAAGGTGGAGTCCTA TTCTAGGGCACTCTG TGTCTTCAAGTGACC AAGGTGGAGTCCTAC TCTAGGGCACTCTGG GTCTTCAAGTGACCT AGGTGGAGTCCTACT CTAGGGCACTCTGGG TCTTCAAGTGACCTG GGTGGAGTCCTACTT TAGGGCACTCTGGGA CTTCAAGTGACCTGT GTGGAGTCCTACTTG AGGGCACTCTGGGAA TTCAAGTGACCTGTA TGGAGTCCTACTTGT GGGCACTCTGGGAAC TCAAGTGACCTGTAC GGAGTCCTACTTGTT GGCACTCTGGGAACC CAAGTGACCTGTACT GAGTCCTACTTGTTT GCACTCTGGGAACCT AAGTGACCTGTACTG AGTCCTACTTGTTTA CACTCTGGGAACCTA AGTGACCTGTACTGC GTCCTACTTGTTTAA ACTCTGGGAACCTAT GTGACCTGTACTGCT TCCTACTTGTTTAAA CTCTGGGAACCTATA TGACCTGTACTGCTT CCTACTTGTTTAAAA TCTGGGAACCTATAA GACCTGTACTGCTTG CTACTTGTTTAAAAA CTGGGAACCTATAAA ACCTGTACTGCTTGG TACTTGTTTAAAAAA TGGGAACCTATAAAG CCTGTACTGCTTGGG ACTTGTTTAAAAAAT GGGAACCTATAAAGG CTGTACTGCTTGGGG CTTGTTTAAAAAATA GGAACCTATAAAGGC TGTACTGCTTGGGGA TTGTTTAAAAAATAT GAACCTATAAAGGCA GTACTGCTTGGGGAC TGTTTAAAAAATATG AACCTATAAAGGCAG TACTGCTTGGGGACT GTTTAAAAAATATGT ACCTATAAAGGCAGG ACTGCTTGGGGACTA TTTAAAAAATATGTA CCTATAAAGGCAGGT CTGCTTGGGGACTAT TTAAAAAATATGTAT CTATAAAGGCAGGTA TGCTTGGGGACTATT TAAAAAATATGTATC TATAAAGGCAGGTAT GCTTGGGGACTATTG AAAAAATATGTATCT ATAAAGGCAGGTATT CTTGGGGACTATTGG AAAAATATGTATCTA TAAAGGCAGGTATTT TTGGGGACTATTGGA AAAATATGTATCTAA AAAGGCAGGTATTTC TGGGGACTATTGGAG AAATATGTATCTAAG AAGGCAGGTATTTCG GGGGACTATTGGAGA AATATGTATCTAAGA AGGCAGGTATTTCGG GGGACTATTGGAGAA ATATGTATCTAAGAA GGCAGGTATTTCGGG GGACTATTGGAGAAA TATGTATCTAAGAAT GCAGGTATTTCGGGC GACTATTGGAGAAAA ATGTATCTAAGAATG CAGGTATTTCGGGCC ACTATTGGAGAAAAT TGTATCTAAGAATGT AGGTATTTCGGGCCC CTATTGGAGAAAATA GTATCTAAGAATGTT GGTATTTCGGGCCCT TATTGGAGAAAATAA TATCTAAGAATGTTC GTATTTCGGGCCCTC ATTGGAGAAAATAAG ATCTAAGAATGTTCT TATTTCGGGCCCTCC TTGGAGAAAATAAGG TCTAAGAATGTTCTA ATTTCGGGCCCTCCT TGGAGAAAATAAGGT CTAAGAATGTTCTAG TTTCGGGCCCTCCTC GGAGAAAATAAGGTG TAAGAATGTTCTAGG TTCGGGCCCTCCTCT GAGAAAATAAGGTGG AAGAATGTTCTAGGG TCGGGCCCTCCTCTT CGGGCCCTCCTCTTC GAAGGCCCAGGATGG GACAGAGAGACGGGA GGGCCCTCCTCTTCA AAGGCCCAGGATGGC ACAGAGAGACGGGAG GGCCCTCCTCTTCAG AGGCCCAGGATGGCT CAGAGAGACGGGAGA GCCCTCCTCTTCAGG GGCCCAGGATGGCTT AGAGAGACGGGAGAG CCCTCCTCTTCAGGA GCCCAGGATGGCTTT GAGAGACGGGAGAGT CCTCCTCTTCACGAA CCCAGGATGGCTTTT AGAGACGGGAGAGTC CTCCTCTTCAGGAAT CCAGGATGGCTTTTG GAGACGGGAGAGTCA TCCTCTTCAGGAATC CAGGATGGCTTTTGC AGACGGGAGAGTCAG CCTCTTCAGGAATCT AGGATGGCTTTTGCT GACGGGAGAGTCAGC CTCTTCAGGAATCTT GGATGGCTTTTGCTG ACGGGAGAGTCAGCC TCTTCAGGAATCTTC GATGGCTTTTGCTGC CGGGAGAGTCAGCCT CTTCAGGAATCTTCC ATGGCTTTTGCTGCG GGGAGAGTCAGCCTC TTCAGGAATCTTCCT TGGCTTTTGCTGCGG GGAGAGTCAGCCTCC TCAGGAATCTTCCTG GGCTTTTGCTGCGGC GAGAGTCAGCCTCCA CAGGAATCTTCCTGA GCTTTTGCTGCGGCC AGAGTCAGCCTCCAC AGGAATCTTCCTGAA CTTTTGCTGCGGCCC GAGTCAGCCTCCACA GGAATCTTCCTGAAG TTTTGCTGCGGCCCC AGTCAGCCTCCACAT GAATCTTCCTGAAGA TTTGCTGCGGCCCCG GTCAGCCTCCACATT AATCTTCCTGAAGAC TTGCTGCGGCCCCGT TCAGCCTCCACATTC ATCTTCCTGAAGACA TGCTGCGGCCCCGTG CAGCCTCCACATTCA TCTTCCTGAAGACAT GCTGCGGCCCCGTGG AGCCTCCACATTCAG CTTCCTGAAGACATG CTGCGGCCCCGTGGG GCCTCCACATTCAGA TTCCTGAAGACATGG TGCGGCCCCGTGGGG CCTCCACATTCAGAG TCCTGAAGACATGGC GCGGCCCCGTGGGGT CTCCACATTCAGAGG CCTGAAGACATGGCC CGGCCCCGTGGGGTA TCCACATTCAGAGGC CTGAAGACATGGCCC GGCCCCGTGGGGTAG CCACATTCAGAGGCA TGAAGACATGGCCCA GCCCCGTGGGGTAGG CACATTCAGAGGCAT GAAGACATGGCCCAG CCCCGTGGGGTAGGA ACATTCAGAGGCATC AAGACATGGCCCAGT CCCGTGGGGTAGGAG CATTCAGAGGCATCA AGACATGGCCCAGTC CCGTGGGGTAGGAGG ATTCAGAGGCATCAC GACATGGCCCAGTCG CGTGGGGTAGGAGGG TTCAGAGGCATCACA ACATGGCCCAGTCGA GTGGGGTAGGAGGGA TCAGAGGCATCACAA CATGGCCCAGTCGAA TGGGGTAGGAGGGAC CAGAGGCATCACAAG ATGGCCCAGTCGAAG GGGGTAGGAGGGACA AGAGGCATCACAAGT TGGCCCAGTCGAAGG GGGTAGGAGGGACAG GAGGCATCACAAGTA GGCCCAGTCGAAGGC GGTAGGAGGGACAGA AGGCATCACAAGTAA GCCCAGTCGAAGGCC GTAGGAGGGACAGAG GGCATCACAAGTAAT CCCAGTCGAAGGCCC TAGGAGGGACAGAGA GCATCACAAGTAATG CCAGTCGAAGGCCCA AGGAGGGACAGAGAG CATCACAAGTAATGG CAGTCGAAGGCCCAG GGAGGGACAGAGAGA ATCACAAGTAATGGC AGTCGAAGGCCCAGG GAGGGACAGAGAGAC TCACAAGTAATGGCA GTCGAAGGCCCAGGA AGGGACAGAGAGACG CACAAGTAATGGCAC TCGAAGGCCCAGGAT GGGACAGAGAGACGG ACAAGTAATGGCACA CGAAGGCCCAGGATG GGACAGAGAGACGGG CAAGTAATGGCACAA AAGTAATGGCACAAT TGTAGTTCAACAACT TCTTTAAAGGCAAAG AGTAATGGCACAATT GTAGTTCAACAACTC CTTTAAAGGCAAAGC GTAATGGCACAATTC TAGTTCAACAACTCA TTTAAAGGCAAAGCT TAATGGCACAATTCT AGTTCAACAACTCAA TTAAAGGCAAAGCTT AATGGCACAATTCTT GTTCAACAACTCAAG TAAAGGCAAAGCTTT ATGGCACAATTCTTC TTCAACAACTCAAGA AAAGGCAAAGCTTTA TGGCACAATTCTTCG TCAACAACTCAAGAC AAGGCAAAGCTTTAT GGCACAATTCTTCGG CAACAACTCAAGACG AGGCAAAGCTTTATT GCACAATTCTTCGGA AACAACTCAAGACGA GGCAAAGCTTTATTT CACAATTCTTCGGAT ACAACTCAAGACGAA GCAAAGCTTTATTTT ACAATTCTTCGGATG CAACTCAAGACGAAG CAAAGCTTTATTTTC CAATTCTTCGGATGA AACTCAAGACGAAGC AAAGCTTTATTTTCA AATTCTTCGGATGAC ACTCAAGACGAAGCT AAGCTTTATTTTCAT ATTCTTCGGATGACT CTCAAGACGAAGCTT AGCTTTATTTTCATC TTCTTCGGATGACTG TCAAGACGAAGCTTA GCTTTATTTTCATCT TCTTCGGATGACTGC CAAGACGAAGCTTAT CTTTATTTTCATCTC CTTCGGATGACTGCA AAGACGAAGCTTATT TTTATTTTCATCTCT TTCGGATGACTGCAG AGACGAAGCTTATTT TTATTTTCATCTCTC TCGGATGACTGCAGA GACGAAGCTTATTTC TATTTTCATCTCTCA CGGATGACTGCAGAA ACGAAGCTTATTTCT ATTTTCATCTCTCAT GGATGACTGCAGAAA CGAAGCTTATTTCTG TTTTCATCTCTCATC GATGACTGCAGAAAA GAAGCTTATTTCTGA TTTCATCTCTCATCT ATGACTGCAGAAAAT AAGCTTATTTCTGAG TTCATCTCTCATCTT TGACTGCAGAAAATA AGCTTATTTCTGAGG TCATCTCTCATCTTT GACTGCAGAAAATAG GCTTATTTCTGAGGA CATCTCTCATCTTTT ACTGCAGAAAATAGT CTTATTTCTGAGGAT ATCTCTCATCTTTTG CTGCAGAAAATAGTG TTATTTCTGAGGATA TCTCTCATCTTTTGT TGCAGAAAATAGTGT TATTTCTGAGGATAA CTCTCATCTTTTGTC GCAGAAAATAGTGTT ATTTCTGAGGATAAG TCTCATCTTTTGTCC CAGAAAATAGTGTTT TTTCTGAGGATAAGC CTCATCTTTTGTCCT AGAAAATAGTGTTTT TTCTGAGGATAAGCT TCATCTTTTGTCCTC GAAAATAGTGTTTTG TCTGAGGATAAGCTC CATCTTTTGTCCTCC AAAATAGTGTTTTGT CTGAGGATAAGCTCT ATCTTTTGTCCTCCT AAATAGTGTTTTGTA TGAGGATAAGCTCTT TCTTTTGTCCTCCTT AATAGTGTTTTGTAG GAGGATAAGCTCTTT CTTTTGTCCTCCTTA ATAGTGTTTTGTAGT AGGATAAGCTCTTTA TTTTGTCCTCCTTAG TAGTGTTTTGTAGTT GGATAAGCTCTTTAA TTTGTCCTCCTTAGC AGTGTTTTGTAGTTC GATAAGCTCTTTAAA TTGTCCTCCTTAGCA GTGTTTTGTAGTTCA ATAAGCTCTTTAAAG TGTCCTCCTTAGCAC TGTTTTGTAGTTCAA TAAGCTCTTTAAAGG GTCCTCCTTAGCACA GTTTTGTAGTTCAAC AAGCTCTTTAAAGGC TCCTCCTTAGCACAA TTTTGTAGTTCAACA AGCTCTTTAAAGGCA CCTCCTTAGCACAAT TTTGTAGTTCAACAA GCTCTTTAAAGGCAA CTCCTTAGCACAATG TTGTAGTTCAACAAC CTCTTTAAAGGCAAA TCCTTAGCACAATGT CCTTAGCACAATGTA GAGGAATGGCTTGCT ATAGAGATTCACCCA CTTAGCACAATGTAA AGGAATGGCTTGCTG TAGAGATTCACCCAT TTAGCACAATGTAAA GGAATGGCTTGCTGG AGAGATTCACCCATG TAGCACAATGTAAAA GAATGGCTTGCTGGG GAGATTCACCCATGT AGCACAATGTAAAAA AATGGCTTGCTGGGG AGATTCACCCATGTT GCACAATGTAAAAAA ATGGCTTGCTGGGGA GATTCACCCATGTTT CACAATGTAAAAAAG TGGCTTGCTGGGGAG ATTCACCCATGTTTG ACAATGTAAAAAAAG GGCTTGCTGGGGAGC TTCACCCATGTTTGT CAATGTAAAAAAGAA GCTTGCTGGGGAGCC TCACCCATGTTTGTT AATGTAAAAAAGAAT CTTGCTGGGGAGCCC CACCCATGTTTGTTG ATGTAAAAAAGAATA TTGCTGGGGAGCCCA ACCCATGTTTGTTGA TGTAPAAAAGAATAG TGCTGGGGAGCCCAT CCCATGTTTGTTGAA GTAAAAAAGAATAGT GCTGGGGAGCCCATC CCATGTTTGTTGAAC TAAAAAAGAATAGTA CTGGGGAGCCCATCC CATGTTTGTTGAACT AAAAAAGAATAGTAA TGGGGAGCCCATCCA ATGTTTGTTGAACTT AAAAAGAATAGTAAT GGGGAGCCCATCCAG TGTTTGTTGAACTTA AAAAGAATAGTAATA GGGAGCCCATCCAGG GTTTGTTGAACTTAG AAAGAATAGTAATAT GGAGCCCATCCAGGA TTTGTTGAACTTAGA AAGAATAGTAATATC GAGCCCATCCAGGAC TTGTTGAACTTAGAG AGAATAGTAATATCA AGCCCATCCAGGACA TGTTGAACTTAGAGT GAATAGTAATATCAG GCCCATCCAGGACAC GTTGAACTTAGAGTC AATAGTAATATCAGA CCCATCCAGGACACT TTGAACTTAGAGTCA ATAGTAATATCAGAA CCATCCAGGACACTG TGAACTTAGAGTCAT TAGTAATATCAGAAC CATCCAGGACACTGG GAACTTAGAGTCATT AGTAATATCAGAACA ATCCAGGACACTGGG AACTTAGAGTCATTC GTAATATCAGAACAG TCCAGGACACTGGGA ACTTAGAGTCATTCT TAATATCAGAACAGG CCAGGACACTGGGAG CTTAGAGTCATTCTC AATATCAGAACAGGA CAGGACACTGGGAGC TTAGAGTCATTCTCA ATATCAGAACAGGAA AGGACACTGGGAGCA TAGAGTCATTCTCAT TATCAGAACAGGAAG GGACACTGGGAGCAC AGAGTCATTCTCATG ATCAGAACAGGAAGG GACACTGGGAGCACA GAGTCATTCTCATGC TCAGAACAGGAAGGA ACACTGGGAGCACAT AGTCATTCTCATGCT CAGAACAGGAAGGAG CACTGGGAGCACATA GTCATTCTCATGCTT AGAACAGGAAGGAGG ACTGGGAGCACATAG TCATTCTCATGCTTT GAACAGGAAGGAGGA CTGGGAGCACATAGA CATTCTCATGCTTTT AACAGGAAGGAGGAA TGGGAGCACATAGAG ATTCTCATGCTTTTC ACAGGAAGGAGGAAT GGGAGCACATAGAGA TTCTCATGCTTTTCT CAGGAAGGAGGAATG GGAGCACATAGAGAT TCTCATGCTTTTCTT AGGAAGGAGGAATGG GAGCACATAGAGATT CTCATGCTTTTCTTT GGAAGGAGGAATGGC AGCACATAGAGATTC TCATGCTTTTCTTTA GAAGGAGGAATGGCT GCACATAGAGATTCA CATGCTTTTCTTTAT AAGGAGGAATGGCTT CACATAGAGATTCAC ATGCTTTTCTTTATA AGGAGGAATGGCTTG ACATAGAGATTCACC TGCTTTTCTTTATAA GGAGGAATGGCTTGC CATAGAGATTCACCC GCTTTTCTTTATAAT CTTTTCTTTATAATT TGTTAACATTGTATA TACTAGATAATCCTA TTTTCTTTATAATTC GTTAACATTGTATAC ACTAGATAATCCTAG TTTCTTTATAATTCA TTAACATTGTATACA CTAGATAATCCTAGA TTCTTTATAATTCAC TAACATTGTATACAA TAGATAATCCTAGAT TCTTTATAATTCACA AACATTGTATACAAC AGATAATCCTAGATG CTTTATAATTCACAC ACATTGTATACAACA GATAATCCTAGATGA TTTATAATTCACACA CATTGTATACAACAT ATAATCCTAGATGAA TTATAATTCACACAT ATTGTATACAACATA TAATCCTAGATGAAA TATAATTCACACATA TTGTATACAACATAG AATCCTAGATGAAAT ATAATTCACACATAT TGTATACAACATAGC ATCCTAGATGAAATG TAATTCACACATATA GTATACAACATAGCC TCCTAGATGAAATGT AATTCACACATATAT TATACAACATAGCCC CCTAGATGAAATGTT ATTCACACATATATG ATACAACATAGCCCC CTAGATGAAATGTTA TTCACACATATATGC TACAACATAGCCCCA TAGATGAAATGTTAG TCACACATATATGCA ACAACATAGCCCCAA AGATGAAATGTTAGA CACACATATATGCAG CAACATAGCCCCAAA GATGAAATGTTAGAG ACACATATATGCAGA AACATAGCCCCAAAT ATGAAATGTTAGAGA CACATATATGCAGAG ACATAGCCCCAAATA TGAAATGTTAGAGAT ACATATATGCAGAGA CATAGCCCCAAATAT GAAATGTTAGAGATG CATATATGCAGAGAA ATAGCCCCAAATATA AAATGTTAGAGATGC ATATATGCAGAGAAG TAGCCCCAAATATAG AATGTTAGAGATGCT TATATGCAGAGAAGA AGCCCCAAATATAGT ATGTTAGAGATGCTA ATATGCAGAGAAGAT GCCCCAAATATAGTA TGTTAGAGATGCTAT TATGCAGAGAAGATA CCCCAAATATAGTAA GTTAGAGATGCTATA ATGCAGAGAAGATAT CCCAAATATAGTAAG TTAGAGATGCTATAT TGCAGAGAAGATATG CCAAATATAGTAAGA TAGAGATGCTATATG GCAGAGAAGATATGT CAAATATAGTAAGAT AGAGATGCTATATGA CAGAGAAGATATGTT AAATATAGTAAGATC GAGATGCTATATGAT AGAGAAGATATGTTC AATATAGTAAGATCT AGATGCTATATGATA GAGAAGATATGTTCT ATATAGTAAGATCTA GATGCTATATGATAC AGAAGATATGTTCTT TATAGTAAGATCTAT ATGCTATATGATACA GAAGATATGTTCTTG ATAGTAAGATCTATA TGCTATATGATACAA AAGATATGTTCTTGT TAGTAAGATCTATAC GCTATATGATACAAC AGATATGTTCTTGTT AGTAAGATCTATACT CTATATGATACAACT GATATGTTCTTGTTA GTAAGATCTATACTA TATATGATACAACTG ATATGTTCTTGTTAA TAAGATCTATACTAG ATATGATACAACTGT TATGTTCTTGTTAAC AAGATCTATACTAGA TATGATACAACTGTG ATGTTCTTGTTAACA AGATCTATACTAGAT ATGATACAACTGTGG TGTTCTTGTTAACAT GATCTATACTAGATA TGATACAACTGTGGC GTTCTTGTTAACATT ATCTATACTAGATAA GATACAACTGTGGCC TTCTTGTTAACATTG TCTATACTAGATAAT ATACAACTGTGGCCA TCTTGTTAACATTGT CTATACTAGATAATC TACAACTGTGGCCAT CTTGTTAACATTGTA TATACTAGATAATCC ACAACTGTGGCCATG TTGTTAACATTGTAT ATACTAGATAATCCT CAACTGTGGCCATGA AACTGTGGCCATGAC GGCTGCTCTCCCGGA AGGCTCAGGGAGACT ACTGTGGCCATGACT GCTGCTCTCCCGGAG GGCTCAGGGAGACTC CTGTGGCCATGACTG CTGCTCTCCCGGAGG GCTCAGGGAGACTCT TGTGGCCATGACTGA TGCTCTCCCGGAGGC CTCAGGGAGACTCTG GTGGCCATGACTGAG GCTCTCCCGGAGGCC TCAGGGAGACTCTGC TGGCCATGACTGAGG CTCTCCCGGAGGCCA CAGGGAGACTCTGCC GGCCATGACTGAGGA TCTCCCGGAGGCCAA AGGGAGACTCTGCCC GCCATGACTGAGGAA CTCCCGGAGGCCAAA GGGAGACTCTGCCCT CCATGACTGAGGAAA TCCCGGAGGCCAAAC GGAGACTCTGCCCTG CATGACTGAGGAAAG CCCGGAGGCCAAACC GAGACTCTGCCCTGC ATGACTGAGGAAAGG CCGGAGGCCAAACCC AGACTCTGCCCTGCT TGACTGAGGAAAGGA CGGAGGCCAAACCCA GACTCTGCCCTGCTG GACTGAGGAAAGGAG GGAGGCCAAACCCAA ACTCTGCCCTGCTGC ACTGAGGAAAGGAGC GAGGCCAAACCCAAG CTCTGCCCTGCTGCA CTGAGGAAAGGAGCT AGGCCAAACCCAAGA TCTGCCCTGCTGCAG TGAGGAAAGGAGCTC GGCCAAACCCAAGAA CTGCCCTGCTGCAGA GAGGAAAGGAGCTCA GCCAAACCCAAGAAG TGCCCTGCTGCAGAC AGGAAAGGAGCTCAC CCAAACCCAAGAAGG GCCCTGCTGCAGACC GGAAAGGAGCTCACG CAAACCCAAGAAGGT CCCTGCTGCAGACCT GAAAGGAGCTCACGC AAACCCAAGAAGGTC CCTGCTGCAGACCTC AAAGGAGCTCACGCC AACCCAAGAAGGTCT CTGCTGCAGACCTCG AAGGAGCTCACGCCC ACCCAAGAAGGTCTG TGCTGCAGACCTCGG AGGAGCTCACGCCCA CCCAAGAAGGTCTGG GCTGCAGACCTCGGT GGAGCTCACGCCCAG CCAAGAAGGTCTGGC CTGCAGACCTCGGTG GAGCTCACGCCCAGA CAAGAAGGTCTGGCA TGCAGACCTCGGTGT AGCTCACGCCCAGAG AAGAAGGTCTGGCAA GCAGACCTCGGTGTG GCTCACGCCCAGAGA AGAAGGTCTGGCAAA CAGACCTCGGTGTGG CTCACGCCCAGAGAC GAAGGTCTGGCAAAG AGACCTCGGTGTGGA TCACGCCCAGAGACT AAGGTCTGGCAAAGT GACCTCGGTGTGGAC CACGCCCAGAGACTG AGGTCTGGCAAAGTC ACCTCGGTGTGGACA ACGCCCAGAGACTGG GGTCTGGCAAAGTCA CCTCGGTGTGGACAC CGCCCAGAGACTGGG GTCTGGCAAAGTCAG CTCGGTGTGGACACA GCCCAGAGACTGGGC TCTGGCAAAGTCAGG TCGGTGTGGACACAC CCCAGAGACTGGGCT CTGGCAAAGTCAGGC CGGTGTGGACACACG CCAGAGACTGGGCTG TGGCAAAGTCAGGCT GGTGTGGACACACGC CAGAGACTGGGCTGC GGCAAAGTCAGGCTC GTGTGGACACACGCT AGAGACTGGGCTGCT GCAAAGTCAGGCTCA TGTGGACACACGCTG GAGACTGGGCTGCTC CAAAGTCAGGCTCAG GTGGACACACGCTGC AGACTGGGCTGCTCT AAAGTCAGGCTCAGG TGGACACACGCTGCA GACTGGGCTGCTCTC AAGTCAGGCTCAGGG GGACACACGCTGCAT ACTGGGCTGCTCTCC AGTCAGGCTCAGGGA GACACACGCTGCATA CTGGGCTGCTCTCCC GTCAGGCTCAGGGAG ACACACGCTGCATAG TGGGCTGCTCTCCCG TCAGGCTCAGGGAGA CACACGCTGCATAGA GGGCTGCTCTCCCGG CAGGCTCAGGGAGAC ACACGCTGCATAGAG CACGCTGCATAGAGC ATTCTGCCTACCTAT GGGGGAAAAGTATTT ACGCTGCATAGAGCT TTCTGCCTACCTATT GGGGAAAAGTATTTT CGCTGCATAGAGCTC TCTGCCTACCTATTA GGGAAAAGTATTTTT GCTGCATAGAGCTCT CTGCCTACCTATTAG GGAAAAGTATTTTTG CTGCATAGAGCTCTC TGCCTACCTATTAGC GAAAAGTATTTTTGA TGCATAGAGCTCTCC GCCTACCTATTAGCT AAAAGTATTTTTGAG GCATAGAGCTCTCCT CCTACCTATTAGCTT AAAGTATTTTTGAGA CATAGAGCTCTCCTT CTACCTATTAGCTTT AAGTATTTTTGAGAA ATAGAGCTCTCCTTG TACCTATTAGCTTTT AGTATTTTTGAGAAG TAGAGCTCTCCTTGA ACCTATTAGCTTTTC GTATTTTTGAGAAGT AGAGCTCTCCTTGAA CCTATTAGCTTTTCT TATTTTTGAGAAGTT GAGCTCTCCTTGAAA CTATTAGCTTTTCTT ATTTTTGAGAAGTTT AGCTCTCCTTGAAAA TATTAGCTTTTCTTT TTTTTGAGAAGTTTG GCTCTCCTTGAAAAC ATTAGCTTTTCTTTA TTTTGAGAAGTTTGT CTCTCCTTGAAAACA TTAGCTTTTCTTTAT TTTGAGAAGTTTGTC TCTCCTTGAAAACAG TAGCTTTTCTTTATT TTGAGAAGTTTGTCT CTCCTTGAAAACAGA AGCTTTTCTTTATTT TGAGAAGTTTGTCTT TCCTTGAAAACAGAG GCTTTTCTTTATTTT GAGAAGTTTGTCTTG CCTTGAAAACAGAGG CTTTTCTTTATTTTT AGAAGTTTGTCTTGC CTTGAAAACAGAGGG TTTTCTTTATTTTTT GAAGTTTGTCTTGCA TTGAAAACAGAGGGG TTTCTTTATTTTTTT AAGTTTGTCTTGCAA TGAAAACAGAGGGGT TTCTTTATTTTTTTA AGTTTGTCTTGCAAT GAAAACAGAGGGGTC TCTTTATTTTTTTAA GTTTGTCTTGCAATG AAAACAGAGGGGTCT CTTTATTTTTTTAAC TTTGTCTTGCAATGT AAACAGAGGGGTCTC TTTATTTTTTTAACT TTGTCTTGCAATGTA AACAGAGGGGTCTCA TTATTTTTTTAACTT TGTCTTGCAATGTAT ACAGAGGGGTCTCAA TATTTTTTTAACTTT GTCTTGCAATGTATT CAGAGGGGTCTCAAG ATTTTTTTAACTTTT TCTTGCAATGTATTT AGAGGGGTCTCAAGA TTTTTTTAACTTTTT CTTGCAATGTATTTA GAGGGGTCTCAAGAC TTTTTTAACTTTTTG TTGCAATGTATTTAT AGGGGTCTCAAGACA TTTTTAACTTTTTGG TGCAATGTATTTATA GGGGTCTCAAGACAT TTTTAACTTTTTGGG GCAATGTATTTATAA GGGTCTCAAGACATT TTTAACTTTTTGGGG CAATGTATTTATAAA GGTCTCAAGACATTC TTAACTTTTTGGGGG AATGTATTTATAAAT GTCTCAAGACATTCT TAACTTTTTGGGGGG ATGTATTTATAAATA TCTCAAGACATTCTG AACTTTTTGGGGGGA TGTATTTATAAATAG CTCAAGACATTCTGC ACTTTTTGGGGGGAA GTATTTATAAATAGT TCAAGACATTCTGCC CTTTTTGGGGGGAAA TATTTATAAATAGTA CAAGACATTCTGCCT TTTTTGGGGGGAAAA ATTTATAAATAGTAA AAGACATTCTGCCTA TTTTGGGGGGAAAAG TTTATAAATAGTAAA AGACATTCTGCCTAC TTTGGGGGGAAAAGT TTATAAATAGTAAAT GACATTCTGCCTACC TTGGGGGGAAAAGTA TATAAATAGTAAATA ACATTCTGCCTACCT TGGGGGGAAAAGTAT ATAAATAGTAAATAA CATTCTGCCTACCTA GGGGGGAAAAGTATT TAAATAGTAAATAAA AAATAGTAAATAAAG AATAGTAAATAAAGT ATAGTAAATAAAGTT TAGTAAATAAAGTTT AGTAAATAAAGTTTT GTAAATAAAGTTTTT TAAATAAAGTTTTTA AAATAAAGTTTTTAC AATAAAGTTTTTACC ATAAAGTTTTTACCA TAAAGTTTTTACCAT AAAGTTTTTACCATT

EXAMPLE 8

Antisense oligonucleotides to IGF-I may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides: TTTTTTTTTTTTTTG ATTTCATCCCAAATA AAGTCTGGCTCCGGA TTTTTTTTTTTTTGA TTTCATCCCAAATAA AGTCTGGCTCCGGAG TTTTTTTTTTTTGAG TTCATCCCAAATAAA GTCTGGCTCCGGAGG TTTTTTTTTTTGAGA TCATCCCAAATAAAA TCTGGCTCCGGAGGA TTTTTTTTTTGAGAA CATCCCAAATAAAAG CTGGCTCCGGAGGAG TTTTTTTTTGAGAAA ATCCCAAATAAAAGG TGGCTCCGGAGGAGG TTTTTTTTGAGAAAG TCCCAAATAAAAGGA GGCTCCGGAGGAGGG TTTTTTTGAGAAAGG CCCAAATAAAAGGAA GCTCCGGAGGAGGGT TTTTTTGAGAAAGGG CCAAATAAAAGGAAT CTCCGGAGGAGGGTC TTTTTGAGAAAGGGA CAAATAAAAGGAATG TCCGGAGGAGGGTCC TTTTGAGAAAGGGAA AAATAAAAGGAATGA CCGGAGGAGGGTCCC TTTGAGAAAGGGAAT AATAAAAGGAATGAA CGGAGGAGGGTCCCC TTGAGAAAGGGAATT ATAAAAGGAATGAAG GGAGGAGGGTCCCCG TGAGAAAGGGAATTT TAAAAGGAATGAAGT GAGGAGGGTCCCCGA GAGAAAGGGAATTTC AAAAGGAATGAAGTC AGGAGGGTCCCCGAC AGAAAGGGAATTTCA AAAGGAATGAAGTCT GGAGGGTCCCCGACC GAAAGGGAATTTCAT AAGGAATGAAGTCTG GAGGOTCCCCGACCT AAAGGGAATTTCATC AGGAATGAAGTCTGG AGGGTCCCCGACCTC AAGGGAATTTCATCC GGAATGAAGTCTGGC GGGTCCCCGACCTCG AGGGAATTTCATCCC GAATGAAGTCTGGCT GGTCCCCGACCTCGC GGGAATTTCATCCCA AATGAAGTCTGGCTC GTCCCCGACCTCGCT GGAATTTCATCCCAA ATGAAGTCTGGCTCC TCCCCGACCTCGCTG GAATTTCATCCCAAA TGAAGTCTGGCTCCG CCCCGACCTCGCTGT AATTTCATCCCAAAT GAAGTCTGGCTCCGG CCCGACCTCGCTGTG CCGACCTCGCTGTGG GCTCTGGCCGACGAG TCCGCAACGACTATC CGACCTCGCTGTGGG CTCTGGCCGACGAGT CCGCAACGACTATCA GACCTCGCTGTGGGG TCTGGCCGACGAGTG CGCAACGACTATCAG ACCTCGCTGTGGGGG CTGGCCGACGAGTGG GCAACGACTATCAGC CCTCGCTGTGGGGGC TGGCCGACGAGTGGA CAACGACTATCAGCA CTCGCTGTGGGGGCT GGCCGACGAGTGGAG AACGACTATCAGCAG TCGCTGTGGGGGCTC GCCGACGAGTGGAGA ACGACTATCAGCAGC CGCTGTGGGGGCTCC CCGACGAGTGGAGAA CGACTATCAGCAGCT GCTGTGGGGGCTCCT CGACGAGTGGAGATA GACTATCAGCAGCTG CTGTGGGGGCTCCTG GACGAGTGGAGAAAT ACTATCAGCAGCTGA TGTGGGGGCTCCTGT ACGAGTGGAGAAATC CTATCAGCAGCTGAA GTGGGGGCTCCTGTT CGAGTGGAGAAATCT TATCAGCAGCTGAAG TGGGGGCTCCTGTTT GAGTGGAGAAATCTG ATCAGCAGCTGAAGC GGGGGCTCCTGTTTC AGTGGAGAAATCTGC TCAGCAGCTGAAGCG GGGGCTCCTGTTTCT GTGGAGAAATCTGCG CAGCAGCTGAAGCGC GGGCTCCTGTTTCTC TGGAGAAATCTGCGG AGCAGCTGAAGCGCC GGCTCCTGTTTCTCT GGAGAAATCTGCGGG GCAGCTGAAGCGCCT GCTCCTGTTTCTCTC GAGAAATCTGCGGGC CAGCTGAAGCGCCTG CTCCTGTTTCTCTCC AGAAATCTGCGGGCC AGCTGAAGCGCCTGG TCCTGTTTCTCTCCG GAAATCTGCGGGCCA GCTGAAGCGCCTGGA CCTGTTTCTCTCCGC AAATCTGCGGGCCAG CTGAAGCGCCTGGAG CTGTTTCTCTCCGCC AATCTGCGGGCCAGG TGAAGCGCCTGGAGA TGTTTCTCTCCGCCG ATCTGCGGGCCAGGC GAAGCGCCTGGAGAA GTTTCTCTCCGCCGC TCTGCGGGCCAGGCA AAGCGCCTGGAGAAC TTTCTCTCCGCCGCG CTGCGGGCCAGGCAT AGCGCCTGGAGAACT TTCTCTCCGCCGCGC TGCGGGCCAGGCATC GCGCCTGGAGAACTG TCTCTCCGCCGCGCT GCGGGCCAGGCATCG CGCCTGGAGAACTGC CTCTCCGCCGCGCTC CGGGCCAGGCATCGA GCCTGGAGAACTGCA TCTCCGCCGCGCTCT GGGCCAGGCATCGAC CCTGGAGAACTGCAC CTCCGCCGCGCTCTC GGCCAGGCATCGACA CTGGAGAACTGCACG TCCGCCGCGCTCTCG GCCAGGCATCGACAT TGGAGAACTGCACGG CCGCCGCGCTCTCGC CCAGGCATCGACATC GGAGAACTGCACGGT CGCCGCGCTCTCGCT CAGGCATCGACATCC GAGAACTGCACGGTG GCCGCGCTCTCGCTC AGGCATCGACATCCG AGAACTGCACGGTGA CCGCGCTCTCGCTCT GGCATCGACATCCGC GAACTGCACGGTGAT CGCGCTCTCGCTCTG GCATCGACATCCGCA AACTGCACGGTGATC GCGCTCTCGCTCTGG CATCGACATCCGCAA ACTGCACGGTGATCG CGCTCTCGCTCTGGC ATCGACATCCGCAAC CTGCACGGTGATCGA GCTCTCGCTCTGGCC TCGACATCCGCAACG TGCACGGTGATCGAG CTCTCGCTCTGGCCG CGACATCCGCAACGA GCACGGTGATCGAGG TCTCGCTCTGGCCGA GACATCCGCAACGAC CACGGTGATCGAGGG CTCGCTCTGGCCGAC ACATCCGCAACGACT ACGGTGATCGAGGGC TCGCTCTGGCCGACG CATCCGCAACGACTA CGGTGATCGAGGGCT CGCTCTGGCCGACGA ATCCGCAACGACTAT GGTGATCGAGGGCTA GTGATCGAGGGCTAC GGACTACCGCAGCTA AGTACTTGCTGCTGT TGATCGAGGGCTACC GACTACCGCAGCTAC GTACTTGCTGCTGTT GATCGAGGGCTACCT ACTACCGCAGCTACC TACTTGCTGCTGTTC ATCGAGGGCTACCTC CTACCGCAGCTACCG ACTTGCTGCTGTTCC TCGAGGGCTACCTCC TACCGCAGCTACCGC CTTGCTGCTGTTCCG CGAGGGCTACCTCCA ACCGCAGCTACCGCT TTGCTGCTGTTCCGA GAGGGCTACCTCCAC CCGCAGCTACCGCTT TGCTGCTGTTCCGAG AGGGCTACCTCCACA CGCAGCTACCGCTTC GCTGCTGTTCCGAGT GGGCTACCTCCACAT GCAGCTACCGCTTCC CTGCTGTTCCGAGTG GGCTACCTCCACATC CAGCTACCGCTTCCC TGCTGTTCCGAGTGG GCTACCTCCACATCC AGCTACCGCTTCCCC GCTGTTCCGAGTGGC CTACCTCCACATCCT GCTACCGCTTCCCCA CTGTTCCGAGTGGCT TACCTCCACATCCTG CTACCGCTTCCCCAA TGTTCCGAGTGGCTG ACCTCCACATCCTGC TACCGCTTCCCCAAG GTTCCGAGTGGCTGG CCTCCACATCCTGCT ACCGCTTCCCCAAGC TTCCGAGTGGCTGGC CTCCACATCCTGCTC CCGCTTCCCCAAGCT TCCGAGTGGCTGGCC TCCACATCCTGCTCA CGCTTCCCCAAGCTC CCGAGTGGCTGGCCT CCACATCCTGCTCAT GCTTCCCCAAGCTCA CGAGTGGCTGGCCTC CACATCCTGCTCATC CTTCCCCAAGCTCAC GAGTGGCTGGCCTCG ACATCCTGCTCATCT TTCCCCAAGCTCACG AGTGGCTGGCCTCGA CATCCTGCTCATCTC TCCCCAAGCTCACGG GTGGCTGGCCTCGAG ATCCTGCTCATCTCC CCCCAAGCTCACGGT TGGCTGGCCTCGAGA TCCTGCTCATCTCCA CCCAAGCTCACGGTC GGCTGGCCTCGAGAG CCTGCTCATCTCCAA CCAAGCTCACGGTCA GCTGGCCTCGAGAGC CTGCTCATCTCCAAG CAAGCTCACGGTCAT CTGGCCTCGAGAGCC TGCTCATCTCCAAGG AAGCTCACGGTCATT TGGCCTCGAGAGCCT GCTCATCTCCAAGGC AGCTCACGGTCATTA GGCCTCGAGAGCCTC CTCATCTCCAAGGCC GCTCACGGTCATTAC GCCTCGAGAGCCTCG TCATCTCCAAGGCCG CTCACGGTCATTACC CCTCGAGAGCCTCGG CATCTCCAAGGCCGA TCACGGTCATTACCG CTCGAGAGCCTCGGA ATCTCCAAGGCCGAG CACGGTCATTACCGA TCGAGAGCCTCGGAG TCTCCAAGGCCGAGG ACGGTCATTACCGAG CGAGAGCCTCGGAGA CTCCAAGGCCGAGGA CGGTCATTACCGAGT GAGAGCCTCGGAGAC TCCAAGGCCGAGGAC GGTCATTACCGAGTA AGAGCCTCGGAGACC CCAAGGCCGAGGACT GTCATTACCGAGTAC GAGCCTCGGAGACCT CAAGGCCGAGGACTA TCATTACCGAGTACT AGCCTCGGAGACCTC AAGGCCGAGGACTAC CATTACCGAGTACTT GCCTCGGAGACCTCT AGGCCGAGGACTACC ATTACCGAGTACTTG CCTCGGAGACCTCTT GGCCGAGGACTACCG TTACCGAGTACTTGC CTCGGAGACCTCTTC GCCGAGGACTACCGC TACCGAGTACTTGCT TCGGAGACCTCTTCC CCGAGGACTACCGCA ACCGAGTACTTGCTG CGGAGACCTCTTCCC CGAGGACTACCGCAG CCGAGTACTTGCTGC GGAGACCTCTTCCCC GAGGACTACCGCAGC CGAGTACTTGCTGCT GAGACCTCTTCCCCA AGGACTACCGCAGCT GAGTACTTGCTGCTG AGACCTCTTCCCCAA GACCTCTTCCCCAAC CTACAACTACGCCCT ATATTGGGCTTTACA ACCTCTTCCCCAACC TACAACTACGCCCTG TATTGGGCTTTACAA CCTCTTCCCCAACCT ACAACTACGCCCTGG ATTGGGCTTTACAAC CTCTTCCCCAACCTC CAACTACGCCCTGGT TTGGGCTTTACAACC TCTTCCCCAACCTCA AACTACGCCCTGGTC TGGGCTTTACAACCT CTTCCCCAACCTCAC ACTACGCCCTGGTCA GGGCTTTACAACCTG TTCCCCAACCTCACG CTACGCCCTGGTCAT GGCTTTACAACCTGA TCCCCAACCTCACGG TACGCCCTGGTCATC GCTTTACAACCTGAG CCCCAACCTCACGGT ACGCCCTGGTCATCT CTTTACAACCTGAGG CCCAACCTCACGGTC CGCCCTGGTCATCTT TTTACAACCTGAGGA CCAACCTCACGGTCA GCCCTGGTCATCTTC TTACAACCTGAGGAA CAACCTCACGGTCAT CCCTGGTCATCTTCG TACAACCTGAGGAAC AACCTCACGGTCATC CCTGGTCATCTTCGA ACAACCTGAGGAACA ACCTCACGGTCATCC CTGGTCATCTTCGAG CAACCTGAGGAACAT CCTCACGGTCATCCG TGGTCATCTTCGAGA AACCTGAGGAACATT CTCACGGTCATCCGC GGTCATCTTCGAGAT ACCTGAGGAACATTA TCACGGTCATCCGCG GTCATCTTCGAGATG CCTGAGGAACATTAC CACGGTCATCCGCGG TCATCTTCGAGATGA CTGAGGAACATTACT ACGGTCATCCGCGGC CATCTTCGAGATGAC TGAGGAACATTACTC CGGTCATCCGCGGCT ATCTTCGAGATGACC GAGGAACATTACTCG GGTCATCCGCGGCTG TCTTCGAGATGACCA AGGAACATTACTCGG GTCATCCGCGGCTGG CTTCGAGATGACCAA GGAACATTACTCGGG TCATCCGCGGCTGGA TTCGAGATGACCAAT GAACATTACTCGGGG CATCCGCGGCTGGAA TCGAGATGACCAATC AACATTACTCGGGGG ATCCGCGGCTGGAAA CGAGATGACCAATCT ACATTACTCGGGGGG TCCGCGGCTGGAAAC GAGATGACCAATCTC CATTACTCGGGGGGC CCGCGGCTGGAAACT AGATGACCAATCTCA ATTACTCGGGGGGCC CGCGGCTGGAAACTC GATGACCAATCTCAA TTACTCGGGGGGCCA GCGGCTGGAAACTCT ATGACCAATCTCAAG TACTCGGGGGGCCAT CGGCTGGAAACTCTT TGACCAATCTCAAGG ACTCGGGGGGCCATC GGCTGGAAACTCTTC GACCAATCTCAAGGA CTCGGGGGGCCATCA GCTGGAAACTCTTCT ACCAATCTCAAGGAT TCGGGGGGCCATCAG CTGGAAACTCTTCTA CCAATCTCAAGGATA CGGGGGGCCATCAGG TGGAAACTCTTCTAC CAATCTCAAGGATAT GGGGGGCCATCAGGA GGAAACTCTTCTACA AATCTCAAGGATATT GGGGGCCATCAGGAT GAAACTCTTCTACAA ATCTCAAGGATATTG GGGGCCATCAGGATT AAACTCTTCTACAAC TCTCAAGGATATTGG GGGCCATCAGGATTG AACTCTTCTACAACT CTCAAGGATATTGGG GGCCATCAGGATTGA ACTCTTCTACAACTA TCAAGGATATTGGGC GCCATCAGGATTGAG CTCTTCTACAACTAC CAAGGATATTGGGCT CCATCAGGATTGAGA TCTTCTACAACTACG AAGGATATTGGGCTT CATCAGGATTGAGAA CTTCTACAACTACGC AGGATATTGGGCTTT ATCAGGATTGAGAAA TTCTACAACTACGCC GGATATTGGGCTTTA TCAGGATTGAGAAAA TCTACAACTACGCCC GATATTGGGCTTTAC CAGGATTGAGAAAAA AGGATTGAGAAAAAT CTGGTCCCTGATCCT GGAATAAGCCCCCAA GGATTGAGAAAAATG TGGTCCCTGATCCTG GAATAAGCCCCCAAA GATTGAGAAAAATGC GGTCCCTGATCCTGG AATAAGCCCCCAAAG ATTGAGAAAAATGCT GTCCCTGATCCTGGA ATAAGCCCCCAAAGG TTGAGAAAAATGCTG TCCCTGATCCTGGAT TAAGCCCCCAAAGGA TGAGAAAAATGCTGA CCCTGATCCTGGATG AAGCCCCCAAAGGAA GAGAAAAATGCTGAC CCTGATCCTGGATGC AGCCCCCAAAGGAAT AGAAAAATGCTGACC CTGATCCTGGATGCG GCCCCCAAAGGAATG GAAAAATGCTGACCT TGATCCTGGATGCGG CCCCCAAAGGAATGT AAAAATGCTGACCTC GATCCTGGATGCGGT CCCCAAAGGAATGTG AAAATGCTGACCTCT ATCCTGGATGCGGTG CCCAAAGGAATGTGG AAATGCTGACCTCTG TCCTGGATGCGGTGT CCAAAGGAATGTGGG AATGCTGACCTCTGT CCTGGATGCGGTGTC CAAAGGAATGTGGGG ATGCTGACCTCTGTT CTGGATGCGGTGTCC AAAGGAATGTGGGGA TGCTGACCTCTGTTA TGGATGCGGTGTCCA AAGGAATGTGGGGAC GCTGACCTCTGTTAC GGATGCGGTGTCCAA AGGAATGTGGGGACC CTGACCTCTGTTACC GATGCGGTGTCCAAT GGAATGTGGGGACCT TGACCTCTGTTACCT ATGCGGTGTCCAATA GAATGTGGGGACCTG GACCTCTGTTACCTC TGCGGTGTCCAATAA AATGTGGGGACCTGT ACCTCTGTTACCTCT GCGGTGTCCAATAAC ATGTGGGGACCTGTG CCTCTGTTACCTCTC CGGTGTCCAATAACT TGTGGGGACCTGTGT CTCTGTTACCTCTCC GGTGTCCAATAACTA GTGGGGACCTGTGTC TCTGTTACCTCTCCA GTGTCCAATAACTAC TGGGGACCTGTGTCC CTGTTACCTCTCCAC TGTCCAATAACTACA GGGGACCTGTGTCCA TGTTACCTCTCCACT GTCCAATAACTACAT GGGACCTGTGTCCAG GTTACCTCTCCACTG TCCAATAACTACATT GGACCTGTGTCCAGG TTACCTCTCCACTGT CCAATAACTACATTG GACCTGTGTCCAGGG TACCTCTCCACTGTG CAATAACTACATTGT ACCTGTGTCCAGGGA ACCTCTCCACTGTGG AATAACTACATTGTG CCTGTGTCCAGGGAC CCTCTCCACTGTGGA ATAACTACATTGTGG CTGTGTCCAGGGACC CTCTCCACTGTGGAC TAACTACATTGTGGG TGTGTCCAGGGACCA TCTCCACTGTGGACT AACTACATTGTGGGG GTGTCCAGGGACCAT CTCCACTGTGGACTG ACTACATTGTGGGGA TGTCCAGGGACCATG TCCACTGTGGACTGG CTACATTGTGGGGAA GTCCAGGGACCATGG CCACTGTGGACTGGT TACATTGTGGGGAAT TCCAGGGACCATGGA CACTGTGGACTGGTC ACATTGTGGGGAATA CCAGGGACCATGGAG ACTGTGGACTGGTCC CATTGTGGGGAATAA CAGGGACCATGGAGG CTGTGGACTGGTCCC ATTGTGGGGAATAAG AGGGACCATGGAGGA TGTGGACTGGTCCCT TTGTGGGGAATAAGC GGGACCATGGAGGAG GTGGACTGGTCCCTG TGTGGGGAATAAGCC GGACCATGGAGGAGA TGGACTGGTCCCTGA GTGGGGAATAAGCCC GACCATGGAGGAGAA GGACTGGTCCCTGAT TGGGGAATAAGCCCC ACCATGGAGGAGAAG GACTGGTCCCTGATC GGGGAATAAGCCCCC CCATGGAGGAGAAGC ACTGGTCCCTGATCC GGGAATAAGCCCCCA CATGGAGGAGAAGCC ATGGAGGAGAAGCCG GTACAACTACCGCTG GCCCAAGCACGTGTG TGGAGGAGAAGCCGA TACAACTACCGCTGC CCCAAGCACGTGTGG GGAGGAGAAGCCGAT ACAACTACCGCTGCT CCAAGCACGTGTGGG GAGGAGAAGCCGATG CAACTACCGCTGCTG CAAGCACGTGTGGGA AGGAGAAGCCGATGT AACTACCGCTGCTGG AAGCACGTGTGGGAA GGAGAAGCCGATGTG ACTACCGCTGCTGGA AGCACGTGTGGGAAG GAGAAGCCGATGTGT CTACCGCTGCTGGAC GCACGTGTGGGAAGC AGAAGCCGATGTGTG TACCGCTGCTGGACC CACGTGTGGGAAGCG GAAGCCGATGTGTGA ACCGCTGCTGGACCA ACGTGTGGGAAGCGG AAGCCGATGTGTGAG CCGCTGCTGGACCAC CGTGTGGGAAGCGGG AGCCGATGTGTGAGA CGCTGCTGGACCACA GTGTGGGAAGCGGGC GCCGATGTGTGAGAA GCTGCTGGACCACAA TGTGGGAAGCGGGCG CCGATGTGTGAGAAG CTGCTGGACCACAAA GTGGGAAGCGGGCGT CGATGTGTGAGAAGA TGCTGGACCACAAAC TGGGAAGCGGGCGTG GATGTGTGAGAAGAC GCTGGACCACAAACC GGGAAGCGGGCGTGC ATGTGTGAGAAGACC CTGGACCACAAACCG GGAAGCGGGCGTGCA TGTGTGAGAAGACCA TGGACCACAAACCGC GAAGCGGGCGTGCAC GTGTGAGAAGACCAC GGACCACAAACCGCT AAGCGGGCGTGCACC TGTGAGAAGACCACC GACCACAAACCGCTG AGCGGGCGTGCACCG GTGAGAAGACCACCA ACCACAAACCGCTGC GCGGGCGTGCACCGA TGAGAAGACCACCAT CCACAAACCGCTGCC CGGGCGTGCACCGAG GAGAAGACCACCATC CACAAACCGCTGCCA GGGCGTGCACCGAGA AGAAGACCACCATCA ACAAACCGCTGCCAG GGCGTGCACCGAGAA GAAGACCACCATCAA CAAACCGCTGCCAGA GCGTGCACCGAGAAC AAGACCACCATCAAC AAACCGCTGCCAGAA CGTGCACCGAGAACA AGACCACCATCAACA AACCGCTGCCAGAAA GTGCACCGAGAACAA GACCACCATCAACAA ACCGCTGCCAGAAAA TGCACCGAGAACAAT ACCACCATCAACAAT CCGCTGCCAGAAAAT GCACCGAGAACAATG CCACCATCAACAATG CGCTGCCAGAAAATG CACCGAGAACAATGA CACCATCAACAATGA GCTGCCAGAAAATGT ACCGAGAACAATGAG ACCATCAACAATGAG CTGCCAGAAAATGTG CCGAGAACAATGAGT CCATCAACAATGAGT TGCCAGAAAATGTGC CGAGAACAATGAGTG CATCAACAATGAGTA GCCAGAAAATGTGCC GAGAACAATGAGTGC ATCAACAATGAGTAC CCAGAAAATGTGCCC AGAACAATGAGTGCT TCAACAATGAGTACA CAGAAAATGTGCCCA GAACAATGAGTGCTG CAACAATGAGTACAA AGAAAATGTGCCCAA AACAATGAGTGCTGC AACAATGAGTACAAC GAAAATGTGCCCAAG ACAATGAGTGCTGCC ACAATGAGTACAACT AAAATGTGCCCAAGC CAATGAGTGCTGCCA CAATGAGTACAACTA AAATGTGCCCAAGCA AATGAGTGCTGCCAC AATGAGTACAACTAC AATGTGCCCAAGCAC ATGAGTGCTGCCACC ATGAGTACAACTACC ATGTGCCCAAGCACG TGAGTGCTGCCACCC TGAGTACAACTACCG TGTGCCCAAGCACGT GAGTGCTGCCACCCC GAGTACAACTACCGC GTGCCCAAGCACGTG AGTGCTGCCACCCCG AGTACAACTACCGCT TGCCCAAGCACGTGT GTGCTGCCACCCCGA TGCTGCCACCCCGAG CGACACGGCCTGTGT TCTGTGTGCCTGCCT GCTGCCACCCCGAGT GACACGGCCTGTGTA CTGTGTGCCTGCCTG CTGCCACCCCGAGTG ACACGGCCTGTGTAG TGTGTGCCTGCCTGC TGCCACCCCGAGTGC CACGGCCTGTGTAGC GTGTGCCTGCCTGCC GCCACCCCGAGTGCC ACGGCCTGTGTAGCT TGTGCCTGCCTGCCC CCACCCCGAGTGCCT CGGCCTGTGTAGCTT GTGCCTGCCTGCCCG CACCCCGAGTGCCTG GGCCTGTGTAGCTTG TGCCTGCCTGCCCGC ACCCCGAGTGCCTGG GCCTGTGTAGCTTGC GCCTGCCTGCCCGCC CCCCGAGTGCCTGGG CCTGTGTAGCTTGCC CCTGCCTGCCCGCCC CCCGAGTGCCTGGGC CTGTGTAGCTTGCCG CTGCCTGCCCGCCCA CCGAGTGCCTGGGCA TGTGTAGCTTGCCGC TGCCTGCCCGCCCAA CGAGTGCCTGGGCAG GTGTAGCTTGCCGCC GCCTGCCCGCCCAAC GAGTGCCTGGGCAGC TGTAGCTTGCCGCCA CCTGCCCGCCCAACA AGTGCCTGGGCAGCT GTAGCTTGCCGCCAC CTGCCCGCCCAACAC GTGCCTGGGCAGCTG TAGCTTGCCGCCACT TGCCCGCCCAACACC TGCCTGGGCAGCTGC AGCTTGCCGCCACTA GCCCGCCCAACACCT GCCTGGGCAGCTGCA GCTTGCCGCCACTAC CCCGCCCAACACCTA CCTGGGCAGCTGCAG CTTGCCGCCACTACT CCGCCCAACACCTAC CTGGGCAGCTGCAGC TTGCCGCCACTACTA CGCCCAACACCTACA TGGGCAGCTGCAGCG TGCCGCCACTACTAC GCCCAACACCTACAG GGGCAGCTGCAGCGC GCCGCCACTACTACT CCCAACACCTACAGG GGCAGCTGCAGCGCG CCGCCACTACTACTA CCAACACCTACAGGT GCAGCTGCAGCGCGC CGCCACTACTACTAT CAACACCTACAGGTT CAGCTGCAGCGCGCC GCCACTACTACTATG AACACCTACAGGTTT AGCTGCAGCGCGCCT CCACTACTACTATGC ACACCTACAGGTTTG GCTGCAGCGCGCCTG CACTACTACTATGCC CACCTACAGGTTTGA CTGCAGCGCGCCTGA ACTACTACTATGCCG ACCTACAGGTTTGAG TGCAGCGCGCCTGAC CTACTACTATGCCGG CCTACAGGTTTGAGG GCAGCGCGCCTGACA TACTACTATGCCGGT CTACAGGTTTGAGGG CAGCGCGCCTGACAA ACTACTATGCCGGTG TACAGGTTTGAGGGC AGCGCGCCTGACAAC CTACTATGCCGGTGT ACAGGTTTGAGGGCT GCGCGCCTGACAACG TACTATGCCGGTGTC CAGGTTTGAGGGCTG CGCGCCTGACAACGA ACTATGCCGGTGTCT AGGTTTGAGGGCTGG GCGCCTGACAACGAC CTATGCCGGTGTCTG GGTTTGAGGGCTGGC CGCCTGACAACGACA TATGCCGGTGTCTGT GTTTGAGGGCTGGCG GCCTGACAACGACAC ATGCCGGTGTCTGTG TTTGAGGGCTGGCGC CCTGACAACGACACG TGCCGGTGTCTGTGT TTGAGGGCTGGCGCT CTGACAACGACACGG GCCGGTGTCTGTGTG TGAGGGCTGGCGCTG TGACAACGACACGGC CCGGTGTCTGTGTGC GAGGGCTGGCGCTGT GACAACGACACGGCC CGGTGTCTGTGTGCC AGGGCTGGCGCTGTG ACAACGACACGGCCT GGTGTCTGTGTGCCT GGGCTGGCGCTGTGT CAACGACACGGCCTG GTGTCTGTGTGCCTG GGCTGGCGCTGTGTG AACGACACGGCCTGT TGTCTGTGTGCCTGC GCTGGCGCTGTGTGG ACGACACGGCCTGTG GTCTGTGTGCCTGCC CTGGCGCTGTGTGGA TGGCGCTGTGTGGAC CGAGAGCAGCGACTC GCATGCAGGAGTGCC GGCGCTGTGTGGACC GAGAGCAGCGACTCC CATGCAGGAGTGCCC GCGCTGTGTGGACCG AGAGCAGCGACTCCG ATGCAGGAGTGCCCC CGCTGTGTGGACCGT GAGCAGCGACTCCGA TGCAGGAGTGCCCCT GCTGTGTGGACCGTG AGCAGCGACTCCGAG GCAGGAGTGCCCCTC CTGTGTGGACCGTGA GCAGCGACTCCGAGG CAGGAGTGCCCCTCG TGTGTGGACCGTGAC CAGCGACTCCGAGGG AGGAGTGCCCCTCGG GTGTGGACCGTGACT AGCGACTCCGAGGGG GGAGTGCCCCTCGGG TGTGGACCGTGACTT GCGACTCCGAGGGGT GAGTGCCCCTCGGGC GTGGACCGTGACTTC CGACTCCGAGGGGTT AGTGCCCCTCGGGCT TGGACCGTGACTTCT GACTCCGAGGGGTTT GTGCCCCTCGGGCTT GGACCGTGACTTCTG ACTCCGAGGGGTTTG TGCCCCTCGGGCTTC GACCGTGACTTCTGC CTCCGAGGGGTTTGT GCCCCTCGGGCTTCA ACCGTGACTTCTGCG TCCGAGGGGTTTGTG CCCCTCGGGCTTCAT CCGTGACTTCTGCGC CCGAGGGGTTTGTGA CCCTCGGGCTTCATC CGTGACTTCTGCGCC CGAGGGGTTTGTGAT CCTCGGGCTTCATCC GTGACTTCTGCGCCA GAGGGGTTTGTGATC CTCGGGCTTCATCCG TGACTTCTGCGCCAA AGGGGTTTGTGATCC TCGGGCTTCATCCGC GACTTCTGCGCCAAC GGGGTTTGTGATCCA CGGGCTTCATCCGCA ACTTCTGCGCCAACA GGGTTTGTGATCCAC GGGCTTCATCCGCAA CTTCTGCGCCAACAT GGTTTGTGATCCACG GGCTTCATCCGCAAC TTCTGCGCCAACATC GTTTGTGATCCACGA GCTTCATCCGCAACG TCTGCGCCAACATCC TTTGTGATCCACGAC CTTCATCCGCAACGG CTGCGCCAACATCCT TTGTGATCCACGACG TTCATCCGCAACGGC TGCGCCAACATCCTC TGTGATCCACGACGG TCATCCGCAACGGCA GCGCCAACATCCTCA GTGATCCACGACGGC CATCCGCAACGGCAG CGCCAACATCCTCAG TGATCCACGACGGCG ATCCGCAACGGCAGC GCCAACATCCTCAGC GATCCACGACGGCGA TCCGCAACGGCAGCC CCAACATCCTCAGCG ATCCACGACGGCGAG CCGCAACGGCAGCCA CAACATCCTCAGCGC TCCACGACGGCGAGT CGCAACGGCAGCCAG AACATCCTCAGCGCC CCACGACGGCGAGTG GCAACGGCAGCCAGA ACATCCTCAGCGCCG CACGACGGCGAGTGC CAACGGCAGCCAGAG CATCCTCAGCGCCGA ACGACGGCGAGTGCA AACGGCAGCCAGAGC ATCCTCAGCGCCGAG CGACGGCGAGTGCAT ACGGCAGCCAGAGCA TCCTCAGCGCCGAGA GACGGCGAGTGCATG CGGCAGCCAGAGCAT CCTCAGCGCCGAGAG ACGGCGAGTGCATGC GGCAGCCAGAGCATG CTCAGCGCCGAGAGC CGGCGAGTGCATGCA GCAGCCAGAGCATGT TCAGCGCCGAGAGCA GGCGAGTGCATGCAG CAGCCAGAGCATGTA CAGCGCCGAGAGCAG GCGAGTGCATGCAGG AGCCAGAGCATGTAC AGCGCCGAGAGCAGC CGAGTGCATGCAGGA GCCAGAGCATGTACT GCGCCGAGAGCAGCG GAGTGCATGCAGGAG CCAGAGCATGTACTG CGCCGAGAGCAGCGA AGTGCATGCAGGAGT CAGAGCATGTACTGC GCCGAGAGCAGCGAC GTGCATGCAGGAGTG AGAGCATGTACTGCA CCGAGAGCAGCGACT TGCATGCAGGAGTGC GAGCATGTACTGCAT AGCATGTACTGCATC TGAGGAAGAAAAGAA CTCAGATGCTCCAAG GCATGTACTGCATCC GAGGAAGAAAAGAAA TCAGATGCTCCAAGG CATGTACTGCATCCC AGGAAGAAAAGAAAA CAGATGCTCCAAGGA ATGTACTGCATCCCT GGAAGAAAAGAAAAC AGATGCTCCAAGGAT TGTACTGCATCCCTT GAAGAAAAGAAAACA GATGCTCCAAGGATG GTACTGCATCCCTTG AAGAAAAGAAAACAA ATGCTCCAAGGATGC TACTGCATCCCTTGT AGAAAAGAAAACAAA TGCTCCAAGGATGCA ACTGCATCCCTTGTG GAAAAGAAAACAAAG GCTCCAAGGATGCAC CTGCATCCCTTGTGA AAAAGAAAACAAAGA CTCCAAGGATGCACC TGCATCCCTTGTGAA AAAGAAAACAAAGAC TCCAAGGATGCACCA GCATCCCTTGTGAAG AAGAAAACAAAGACC CCAAGGATGCACCAT CATCCCTTGTGAAGG AGAAAACAAAGACCA CAAGGATGCACCATC ATCCCTTGTGAAGGT GAAAACAAAGACCAT AAGGATGCACCATCT TCCCTTGTGAAGGTC AAAACAAAGACCATT AGGATGCACCATCTT CCCTTGTGAAGGTCC AAACAAAGACCATTG GGATGCACCATCTTC CCTTGTGAAGGTCCT AACAAAGACCATTGA GATGCACCATCTTCA CTTGTGAAGGTCCTT ACAAAGACCATTGAT ATGCACCATCTTCAA TTGTGAAGGTCCTTG CAAAGACCATTGATT TGCACCATCTTCAAG TGTGAAGGTCCTTGC AAAGACCATTGATTC GCACCATCTTCAAGG GTGAAGGTCCTTGCC AAGACCATTGATTCT CACCATCTTCAAGGG TGAAGGTCCTTGCCC AGACCATTGATTCTG ACCATCTTCAAGGGC GAAGGTCCTTGCCCG GACCATTGATTCTGT CCATCTTCAAGGGCA AAGGTCCTTGCCCGA ACCATTGATTCTGTT CATCTTCAAGGGCAA AGGTCCTTGCCCGAA CCATTGATTCTGTTA ATCTTCAAGGGCAAT GGTCCTTGCCCGAAG CATTGATTCTGTTAC TCTTCAAGGGCAATT GTCCTTGCCCGAAGG ATTGATTCTGTTACT CTTCAAGGGCAATTT TCCTTGCCCGAAGGT TTGATTCTGTTACTT TTCAAGGGCAATTTG CCTTGCCCGAAGGTC TGATTCTGTTACTTC TCAAGGGCAATTTGC CTTGCCCGAAGGTCT GATTCTGTTACTTCT CAAGGGCAATTTGCT TTGCCCGAAGGTCTG ATTCTGTTACTTCTG AAGGGCAATTTGCTC TGCCCGAAGGTCTGT TTCTGTTACTTCTGC AGGGCAATTTGCTCA GCCCGAAGGTCTGTG TCTGTTACTTCTGCT GGGCAATTTGCTCAT CCCGAAGGTCTGTGA CTGTTACTTCTGCTC GGCAATTTGCTCATT CCGAAGGTCTGTGAG TGTTACTTCTGCTCA GCAATTTGCTCATTA CGAAGGTCTGTGAGG GTTACTTCTGCTCAG CAATTTGCTCATTAA GAAGGTCTGTGAGGA TTACTTCTGCTCAGA AATTTGCTCATTAAC AAGGTCTGTGAGGAA TACTTCTGCTCAGAT ATTTGCTCATTAACA AGGTCTGTGAGGAAG ACTTCTGCTCAGATG TTTGCTCATTAACAT GGTCTGTGAGGAAGA CTTCTGCTCAGATGC TTGCTCATTAACATC GTCTGTGAGGAAGAA TTCTGCTCAGATGCT TGCTCATTAACATCC TCTGTGAGGAAGAAA TCTGCTCAGATGCTC GCTCATTAACATCCG CTGTGAGGAAGAAAA CTGCTCAGATGCTCC CTCATTAACATCCGA TGTGAGGAAGAAAAG TGCTCAGATGCTCCA TCATTAACATCCGAC GTGAGGAAGAAAAGA GCTCAGATGCTCCAA CATTAACATCCGACG ATTAACATCCGACGG CTTCATGGGGCTCAT GCCATTCTCATGCCT TTAACATCCGACGGG TTCATGGGGCTCATC CCATTCTCATGCCTT TAACATCCGACGGGG TCATGGGGCTCATCG CATTCTCATGCCTTG AACATCCGACGGGGG CATGGGGCTCATCGA ATTCTCATGCCTTGG ACATCCGACGGGGGA ATGGGGCTCATCGAG TTCTCATGCCTTGGT CATCCGACGGGGGAA TGGGGCTCATCGAGG TCTCATGCCTTGGTC ATCCGACGGGGGAAT GGGGCTCATCGAGGT CTCATGCCTTGGTCT TCCGACGGGGGAATA GGGCTCATCGAGGTG TCATGCCTTGGTCTC CCGACGGGGGAATAA GGCTCATCGAGGTGG CATGCCTTGGTCTCC CGACGGGGGAATAAC GCTCATCGAGGTGGT ATGCCTTGGTCTCCT GACGGGGGAATAACA CTCATCGAGGTGGTG TGCCTTGGTCTCCTT ACGGGGGAATAACAT TCATCGAGGTGGTGA GCCTTGGTCTCCTTG CGGGGGAATAACATT CATCGAGGTGGTGAC CCTTGGTCTCCTTGT GGGGGAATAACATTG ATCGAGGTGGTGACG CTTGGTCTCCTTGTC GGGGAATAACATTGC TCGAGGTGGTGACGG TTGGTCTCCTTGTCC GGGAATAACATTGCT CGAGGTGGTGACGGG TGGTCTCCTTGTCCT GGAATAACATTGCTT GAGGTGGTGACGGGC GGTCTCCTTGTCCTT GAATAACATTGCTTC AGGTGGTGACGGGCT GTCTCCTTGTCCTTC AATAACATTGCTTCA GGTGGTGACGGGCTA TCTCCTTGTCCTTCC ATAACATTGCTTCAG GTGGTGACGGGCTAC CTCCTTGTCCTTCCT TAACATTGCTTCAGA TGGTGACGGGCTACG TCCTTGTCCTTCCTA AACATTGCTTCAGAG GGTGACGGGCTACGT CCTTGTCCTTCCTAA ACATTGCTTCAGAGC GTGACGGGCTACGTG CTTGTCCTTCCTAAA CATTGCTTCAGAGCT TGACGGGCTACGTGA TTGTCCTTCCTAAAA ATTGCTTCAGAGCTG GACGGGCTACGTGAA TGTCCTTCCTAAAAA TTGCTTCAGAGCTGG ACGGGCTACGTGAAG GTCCTTCCTAAAAAA TGCTTCAGAGCTGGA CGGGCTACGTGAAGA TCCTTCCTAAAAAAC GCTTCAGAGCTGGAG GGGCTACGTGAAGAT CCTTCCTAAAAAACC CTTCAGAGCTGGAGA GGCTACGTGAAGATC CTTCCTAAAAAACCT TTCAGAGCTGGAGAA GCTACGTGAAGATCC TTCCTAAAAAACCTT TCAGAGCTGGAGAAC CTACGTGAAGATCCG TCCTAAAAAACCTTC CAGAGCTGGAGAACT TACGTGAAGATCCGC CCTAAAAAACCTTCG AGAGCTGGAGAACTT ACGTGAAGATCCGCC CTAAAAAACCTTCGC GAGCTGGAGAACTTC CGTGAAQATCCGCCA TAAAAAACCTTCGCC AGCTGGAGAACTTCA GTGAAGATCCGCCAT AAAAAACCTTCGCCT GCTGGAGAACTTCAT TGAAGATCCGCCATT AAAAACCTTCGCCTC CTGGAGAACTTCATG GAAGATCCGCCATTC AAAACCTTCGCCTCA TGGAGAACTTCATGG AAGATCCGCCATTCT AAACCTTCGCCTCAT GGAGAACTTCATGGG AGATCCGCCATTCTC AACCTTCGCCTCATC GAGAACTTCATGGGG GATCCGCCATTCTCA ACCTTCGCCTCATCC AGAACTTCATGGGGC ATCCGCCATTCTCAT CCTTCGCCTCATCCT GAACTTCATGGGGCT TCCGCCATTCTCATG CTTCGCCTCATCCTA AACTTCATGGGGCTC CCGCCATTCTCATGC TTCGCCTCATCCTAG ACTTCATGGGGCTCA CGCCATTCTCATGCC TCGCCTCATCCTAGG CGCCTCATCCTAGGA CTACGTCCTCGACAA ACCACCGCAACCTGA GCCTCATCCTAGGAG TACGTCCTCGACAAC CCACCGCAACCTGAC CCTCATCCTAGGAGA ACGTCCTCGACAACC CACCGCAACCTGACC CTCATCCTAGGAGAG CGTCCTCGACAACCA ACCGCAACCTGACCA TCATCCTAGGAGAGG GTCCTCGACAACCAG CCGCAACCTGACCAT CATCCTAGGAGAGGA TCCTCGACAACCAGA CGCAACCTGACCATC ATCCTAGGAGAGGAG CCTCGACAACCAGAA GCAACCTGACCATCA TCCTAGGAGAGGAGC CTCGACAACCAGAAC CAACCTGACCATCAA CCTAGGAGAGGAGCA TCGACAACCAGAACT AACCTGACCATCAAA CTAGGAGAGGAGCAG CGACAACCAGAACTT ACCTGACCATCAAAG TAGGAGAGGAGCAGC GACAACCAGAACTTG CCTGACCATCAAAGC AGGAGAGGAGCAGCT ACAACCAGAACTTGC CTGACCATCAAAGCA GGAGAGGAGCAGCTA CAACCAGAACTTGCA TGACCATCAAAGCAG GAGAGGAGCAGCTAG AACCAGAACTTGCAG GACCATCAAAGCAGG AGAGGAGCAGCTAGA ACCAGAACTTGCAGC ACCATCAAAGCAGGG GAGGAGCAGCTAGAA CCAGAACTTGCAGCA CCATCAAAGCAGGGA AGGAGCAGCTAGAAG CAGAACTTGCAGCAA CATCAAAGCAGGGAA GGAGCAGCTAGAAGG AGAACTTGCAGCAAC ATCAAAGCAGGGAAA GAGCAGCTAGAAGGG GAACTTGCAGCAACT TCAAAGCAGGGAAAA AGCAGCTAGAAGGGA AACTTGCAGCAACTG CAAAGCAGGGAAAAT GCAGCTAGAAGGGAA ACTTGCAGCAACTGT AAAGCAGGGAAAATG CAGCTAGAAGGGAAT CTTGCAGCAACTGTG AAGCAGGGAAAATGT AGCTAGAAGGGAATT TTGCAGCAACTGTGG AGCAGGGAAAATGTA GCTAGAAGGGAATTA TGCAGCAACTGTGGG GCAGGGAAAATGTAC CTAGAAGGGAATTAC GCAGCAACTGTGGGA CAGGGAAAATGTACT TAGAAGGGAATTACT CAGCAACTGTGGGAC AGGGAAAATGTACTT AGAAGGGAATTACTC AGCAACTGTGGGACT GGGAAAATGTACTTT GAAGGGAATTACTCC GCAACTGTGGGACTG GGAAAATGTACTTTG AAGGGAATTACTCCT CAACTGTGGGACTGG GAAAATGTACTTTGC AGGGAATTACTCCTT AACTGTGGGACTGGG AAAATGTACTTTGCT GGGAATTACTCCTTC ACTGTGGGACTGGGA AAATGTACTTTGCTT GGAATTACTCCTTCT CTGTGGGACTGGGAC AATGTACTTTGCTTT GAATTACTCCTTCTA TGTGGGACTGGGACC ATGTACTTTGCTTTC AATTACTCCTTCTAC GTGGGACTGGGACCA TGTACTTTGCTTTCA ATTACTCCTTCTACG TGGGACTGGGACCAC GTACTTTGCTTTCAA TTACTCCTTCTACGT GGGACTGGGACCACC TACTTTGCTTTCAAT TACTCCTTCTACGTC GGACTGGGACCACCG ACTTTGCTTTCAATC ACTCCTTCTACGTCC GACTGGGACCACCGC CTTTGCTTTCAATCC CTCCTTCTACGTCCT ACTGGGACCACCGCA TTTGCTTTCAATCCC TCCTTCTACGTCCTC CTGGGACCACCGCAA TTGCTTTCAATCCCA CCTTCTACGTCCTCG TGGGACCACCGCAAC TGCTTTCAATCCCAA CTTCTACGTCCTCGA GGGACCACCGCAACC GCTTTCAATCCCAAA TTCTACGTCCTCGAC GGACCACCGCAACCT CTTTCAATCCCAAAT TCTACGTCCTCGACA GACCACCGCAACCTG TTTCAATCCCAAATT TTCAATCCCAAATTA AGTGACGGGGACTAA CCAGGAACAACGGGG TCAATCCCAAATTAT GTGACGGGGACTAAA CAGGAACAACGGGGA CAATCCCAAATTATG TGACGGGGACTAAAG AGGAACAACGGGGAG AATCCCAAATTATGT GACGGGGACTAAAGG GGAACAACGGGGAGA ATCCCAAATTATGTG ACGGGGACTAAAGGG GAACAACGGGGAGAG TCCCAAATTATGTGT CGGGGACTAAAGGGC AACAACGGGGAGAGA CCCAAATTATGTGTT GGGGACTAAAGGGCG ACAACGGGGAGAGAG CCAAATTATGTGTTT GGGACTAAAGGGCGC CAACGGGGAGAGAGC CAAATTATGTGTTTC GGACTAAAGGGCGCC AACGGGGAGAGAGCC AAATTATGTGTTTCC GACTAAAGGGCGCCA ACGGGGAGAGAGCCT AATTATGTGTTTCCG ACTAAAGGGCGCCAA CGGGGAGAGAGCCTC ATTATGTGTTTCCGA CTAAAGGGCGCCAAA GGGGAGAGAGCCTCC TTATGTGTTTCCGAA TAAAGGGCGCCAAAG GGGAGAGAGCCTCCT TATGTGTTTCCGAAA AAAGGGCGCCAAAGC GGAGAGAGCCTCCTG ATGTGTTTCCGAAAT AAGGGCGCCAAAGCA GAGAGAGCCTCCTGT TGTGTTTCCGAAATT AGGGCGCCAAAGCAA AGAGAGCCTCCTGTG GTGTTTCCGAAATTT GGGCGCCAAAGCAAA GAGAGCCTCCTGTGA TGTTTCCGAAATTTA GGCGCCAAAGCAAAG AGAGCCTCCTGTGAA GTTTCCGAAATTTAC GCGCCAAAGCAAAGG GAGCCTCCTGTGAAA TTTCCGAAATTTACC CGCCAAAGCAAAGGG AGCCTCCTGTGAAAG TTCCGAAATTTACCG GCCAAAGCAAAGGGG GCCTCCTGTGAAAGT TCCGAAATTTACCGC CCAAAGCAAAGGGGA CCTCCTGTGAAAGTG CCGAAATTTACCGCA CAAAGCAAAGGGGAC CTCCTGTGAAAGTGA CGAAATTTACCGCAT AAAGCAAAGGGGACA TCCTGTGAAAGTGAC GAAATTTACCGCATG AAGCAAAGGGGACAT CCTGTGAAAGTGACG AAATTTACCGCATGG AGCAAAGGGGACATA CTGTGAAAGTGACGT AATTTACCGCATGGA GCAAAGGGGACATAA TGTGAAAGTGACGTC ATTTACCGCATGGAG CAAAGGGGACATAAA GTGAAAGTGACGTCC TTTACCGCATGGAGG AAAGGGGACATAAAC TGAAAGTGACGTCCT TTACCGCATGGAGGA AAGGGGACATAAACA GAAAGTGACGTCCTG TACCGCATGGAGGAA AGGGGACATAAACAC AAAGTGACGTCCTGC ACCGCATGGAGGAAG GGGGACATAAACACC AAGTGACGTCCTGCA CCGCATGGAGGAAGT GGGACATAAACACCA AGTGACGTCCTGCAT CGCATGGAGGAAGTG GGACATAAACACCAG GTGACGTCCTGCATT GCATGGAGGAAGTGA GACATAAACACCAGG TGACGTCCTGCATTT CATGGAGGAAGTGAC ACATAAACACCAGGA GACGTCCTGCATTTC ATGGAGGAAGTGACG CATAAACACCAGGAA ACGTCCTGCATTTCA TGGAGGAAGTGACGG ATAAACACCAGGAAC CGTCCTGCATTTCAC GGAGGAAGTGACGGG TAAACACCAGGAACA GTCCTGCATTTCACC GAGGAAGTGACGGGG AAACACCAGGAACAA TCCTGCATTTCACCT AGGAAGTGACGGGGA AACACCAGGAACAAC CCTGCATTTCACCTC GGAAGTGACGGGGAC ACACCAGGAACAACG CTGCATTTCACCTCC GAAGTGACGGGGACT CACCAGGAACAACGG TGCATTTCACCTCCA AAGTGACGGGGACTA ACCAGGAACAACGGG GCATTTCACCTCCAC CATTTCACCTCCACC CTGGCACCGGTACCG TCACCGTTTACTACA ATTTCACCTCCACCA TGGCACCGGTACCGG CACCGTTTACTACAA TTTCACCTCCACCAC GGCACCGGTACCGGC ACCGTTTACTACAAG TTCACCTCCACCACC GCACCGGTACCGGCC CCGTTTACTACAAGG TCACCTCCACCACCA CACCGGTACCGGCCC CGTTTACTACAAGGA CACCTCCACCACCAC ACCGGTACCGGCCCC GTTTACTACAAGGAA ACCTCCACCACCACG CCGGTACCGGCCCCC TTTACTACAAGGAAG CCTCCACCACCACGT CGGTACCGGCCCCCT TTACTACAAGGAAGC CTCCACCACCACGTC GGTACCGGCCCCCTG TACTACAAGGAAGCA TCCACCACCACGTCG GTACCGGCCCCCTGA ACTACAAGGAAGCAC CCACCACCACGTCGA TACCGGCCCCCTGAC CTACAAGGAAGCACC CACCACCACGTCGAA ACCGGCCCCCTGACT TACAAGGAAGCACCC ACCACCACGTCGAAG CCGGCCCCCTGACTA ACAAGGAAGCACCCT CCACCACGTCGAAGA CGGCCCCCTGACTAC CAAGGAAGCACCCTT CACCACGTCGAAGAA GGCCCCCTGACTACA AAGGAAGCACCCTTT ACCACGTCGAAGAAT GCCCCCTGACTACAG AGGAAGCACCCTTTA CCACGTCGAAGAATC CCCCCTGACTACAGG GGAAGCACCCTTTAA CACGTCGAAGAATCG CCCCTGACTACAGGG GAAGCACCCTTTAAG ACGTCGAAGAATCGC CCCTGACTACAGGGA AAGCACCCTTTAAGA CGTCGAAGAATCGCA CCTGACTACAGGGAT AGCACCCTTTAAGAA GTCGAAGAATCGCAT CTGACTACAGGGATC GCACCCTTTAAGAAT TCGAAGAATCGCATC TGACTACAGGGATCT CACCCTTTAAGAATG CGAAGAATCGCATCA GACTACAGGGATCTC ACCCTTTAAGAATGT GAAGAATCGCATCAT ACTACAGGGATCTCA CCCTTTAAGAATGTC AAGAATCGCATCATC CTACAGGGATCTCAT CCTTTAAGAATGTCA AGAATCGCATCATCA TACAGGGATCTCATC CTTTAAGAATGTCAC GAATCGCATCATCAT ACAGGGATCTCATCA TTTAAGAATGTCACA AATCGCATCATCATA CAGGGATCTCATCAG TTAAGAATGTCACAG ATCGCATCATCATAA AGGGATCTCATCAGC TAAGAATGTCACAGA TCGCATCATCATAAC GGGATCTCATCAGCT AAGAATGTCACAGAG CGCATCATCATAACC GGATCTCATCAGCTT AGAATGTCACAGAGT GCATCATCATAACCT GATCTCATCAGCTTC GAATGTCACAGAGTA CATCATCATAACCTG ATCTCATCAGCTTCA AATGTCACAGAGTAT ATCATCATAACCTGG TCTCATCAGCTTCAC ATGTCACAGAGTATG TCATCATAACCTGGC CTCATCAGCTTCACC TGTCACAGAGTATGA CATCATAACCTGGCA TCATCAGCTTCACCG GTCACAGAGTATGAT ATCATAACCTGGCAC CATCAGCTTCACCGT TCACAGAGTATGATG TCATAACCTGGCACC ATCAGCTTCACCGTT CACAGAGTATGATGG CATAACCTGGCACCG TCAGCTTCACCGTTT ACAGAGTATGATGGG ATAACCTGGCACCGG CAGCTTCACCGTTTA CAGAGTATGATGGGC TAACCTGGCACCGGT AGCTTCACCGTTTAC AGAGTATGATGGGCA AACCTGGCACCGGTA GCTTCACCGTTTACT GAGTATGATGGGCAG ACCTGGCACCGGTAC CTTCACCGTTTACTA AGTATGATGGGCAGG CCTGGCACCGGTACC TTCACCGTTTACTAC GTATGATGGGCAGGA TATGATGGGCAGGAT GGACGTGGACCTCCC TACTACATGGGCTGA ATGATGGGCAGGATG GACGTGGACCTCCCG ACTACATGGGCTGAA TGATGGGCAGGATGC ACGTGGACCTCCCGC CTACATGGGCTGAAG GATGGGCAGGATGCC CGTGGACCTCCCGCC TACATGGGCTGAAGC ATGGGCAGGATGCCT GTGGACCTCCCGCCC ACATGGGCTGAAGCC TGGGCAGGATGCCTG TGGACCTCCCGCCCA CATGGGCTGAAGCCC GGGCAGGATGCCTGC GGACCTCCCGCCCAA ATGGGCTGAAGCCCT GGCAGGATGCCTGCG GACCTCCCGCCCAAC TGGGCTGAAGCCCTG GCAGGATGCCTGCGG ACCTCCCGCCCAACA GGGCTGAAGCCCTGG CAGGATGCCTGCGGC CCTCCCGCCCAACAA GGCTGAAGCCCTGGA AGGATGCCTGCGGCT CTCCCGCCCAACAAG GCTGAAGCCCTGGAC GGATGCCTGCGGCTC TCCCGCCCAACAAGG CTGAAGCCCTGGACT GATGCCTGCGGCTCC CCCGCCCAACAAGGA TGAAGCCCTGGACTC ATGCCTGCGGCTCCA CCGCCCAACAAGGAC GAAGCCCTGGACTCA TGCCTGCGGCTCCAA CGCCCAACAAGGACG AAGCCCTGGACTCAG GCCTGCGGCTCCAAC GCCCAACAAGGACGT AGCCCTGGACTCAGT CCTGCGGCTCCAACA CCCAACAAGGACGTG GCCCTGGACTCAGTA CTGCGGCTCCAACAG CCAACAAGGACGTGG CCCTGGACTCAGTAC TGCGGCTCCAACAGC CAACAAGGACGTGGA CCTGGACTCAGTACG GCGGCTCCAACAGCT AACAAGGACGTGGAG CTGGACTCAGTACGC CGGCTCCAACAGCTG ACAAGGACGTGGAGC TGGACTCAGTACGCC GGCTCCAACAGCTGG CAAGGACGTGGAGCC GGACTCAGTACGCCG GCTCCAACAGCTGGA AAGGACGTGGAGCCC GACTCAGTACGCCGT CTCCAACAGCTGGAA AGGACGTGGAGCCCG ACTCAGTACGCCGTT TCCAACAGCTGGAAC GGACGTGGAGCCCGG CTCAGTACGCCGTTT CCAACAGCTGGAACA GACGTGGAGCCCGGC TCAGTACGCCGTTTA CAACAGCTGGAACAT ACGTGGAGCCCGGCA CAGTACGCCGTTTAC AACAGCTGGAACATG CGTGGAGCCCGGCAT AGTACGCCGTTTACG ACAGCTGGAACATGG GTGGAGCCCGGCATC GTACGCCGTTTACGT CAGCTGGAACATGGT TGGAGCCCGGCATCT TACGCCGTTTACGTC AGCTGGAACATGGTG GGAGCCCGGCATCTT ACGCCGTTTACGTCA GCTGGAACATGGTGG GAGCCCGGCATCTTA CGCCGTTTACGTCAA CTGGAACATGGTGGA AGCCCGGCATCTTAC GCCGTTTACGTCAAG TGGAACATGGTGGAC GCCCGGCATCTTACT CCGTTTACGTCAAGG GGAACATGGTGGACG CCCGGCATCTTACTA CGTTTACGTCAAGGC GAACATGGTGGACGT CCGGCATCTTACTAC GTTTACGTCAAGGCT AACATGGTGGACGTG CGGCATCTTACTACA TTTACGTCAAGGCTG ACATGGTGGACGTGG GGCATCTTACTACAT TTACGTCAAGGCTGT CATGGTGGACGTGGA GCATCTTACTACATG TACGTCAAGGCTGTG ATGGTGGACGTGGAC CATCTTACTACATGG ACGTCAAGGCTGTGA TGGTGGACGTGGACC ATCTTACTACATGGG CGTCAAGGCTGTGAC GGTGGACGTGGACCT TCTTACTACATGGGC GTCAAGGCTGTGACC GTGGACGTGGACCTC CTTACTACATGGGCT TCAAGGCTGTGACCC TGGACGTGGACCTCC TTACTACATGGGCTG CAAGGCTGTGACCCT AAGGCTGTGACCCTC GGCCAAGAGTGAGAT CTTCCATTCCCTTGG AGGCTGTGACCCTCA GCCAAGAGTGAGATC TTCCATTCCCTTGGA GGCTGTGACCCTCAC CCAAGAGTGAGATCT TCCATTCCCTTGGAC GCTGTGACCCTCACC CAAGAGTGAGATCTT CCATTCCCTTGGACG CTGTGACCCTCACCA AAGAGTGAGATCTTG CATTCCCTTGGACGT TGTGACCCTCACCAT AGAGTGAGATCTTGT ATTCCCTTGGACGTT GTGACCCTCACCATG GAGTGAGATCTTGTA TTCCCTTGGACGTTC TGACCCTCACCATGG AGTGAGATCTTGTAC TCCCTTGGACGTTCT GACCCTCACCATGGT GTGAGATCTTGTACA CCCTTGGACGTTCTT ACCCTCACCATGGTG TGAGATCTTGTACAT CCTTGGACGTTCTTT CCCTCACCATGGTGG GAGATCTTGTACATT CTTGGACGTTCTTTC CCTCACCATGGTGGA AGATCTTGTACATTC TTGGACGTTCTTTCA CTCACCATGGTGGAG GATCTTGTACATTCG TGGACGTTCTTTCAG TCACCATGGTGGAGA ATCTTGTACATTCGC GGACGTTCTTTCAGC CACCATGGTGGAGAA TCTTGTACATTCGCA GACGTTCTTTCAGCA ACCATGGTGGAGAAC CTTGTACATTCGCAC ACGTTCTTTCAGCAT CCATGGTGGAGAACG TTGTACATTCGCACC CGTTCTTTCAGCATC CATGGTGGAGAACGA TGTACATTCGCACCA GTTCTTTCAGCATCG ATGGTGGAGAACGAC GTACATTCGCACCAA TTCTTTCAGCATCGA TGGTGGAGAACGACC TACATTCGCACCAAT TCTTTCAGCATCGAA GGTGGAGAACGACCA ACATTCGCACCAATG CTTTCAGCATCGAAC GTGGAGAACGACCAT CATTCGCACCAATGC TTTCAGCATCGAACT TGGAGAACGACCATA ATTCGCACCAATGCT TTCAGCATCGAACTC GGAGAACGACCATAT TTCGCACCAATGCTT TCAGCATCGAACTCC GAGAACGACCATATC TCGCACCAATGCTTC CAGCATCGAACTCCT AGAACGACCATATCC CGCACCAATGCTTCA AGCATCGAACTCCTC GAACGACCATATCCG GCACCAATGCTTCAG GCATCGAACTCCTCT AACGACCATATCCGT CACCAATGCTTCAGT CATCGAACTCCTCTT ACGACCATATCCGTG ACCAATGCTTCAGTT ATCGAACTCCTCTTC CGACCATATCCGTGG CCAATGCTTCAGTTC TCGAACTCCTCTTCT GACCATATCCGTGGG CAATGCTTCAGTTCC CGAACTCCTCTTCTC ACCATATCCGTGGGG AATGCTTCAGTTCCT GAACTCCTCTTCTCA CCATATCCGTGGGGC ATGCTTCAGTTCCTT AACTCCTCTTCTCAG CATATCCGTGGGGCC TGCTTCAGTTCCTTC ACTCCTCTTCTCAGT ATATCCGTGGGGCCA GCTTCAGTTCCTTCC CTCCTCTTCTCAGTT TATCCGTGGGGCCAA CTTCAGTTCCTTCCA TCCTCTTCTCAGTTA ATCCGTGGGGCCAAG TTCAGTTCCTTCCAT CCTCTTCTCAGTTAA TCCGTGGGGCCAAGA TCAGTTCCTTCCATT CTCTTCTCAGTTAAT CCGTGGGGCCAAGAG CAGTTCCTTCCATTC TCTTCTCAGTTAATC CGTGGGGCCAAGAGT AGTTCCTTCCATTCC CTTCTCAGTTAATCG GTGGGGCCAAGAGTG GTTCCTTCCATTCCC TTCTCAGTTAATCGT TGGGGCCAAGAGTGA TTCCTTCCATTCCCT TCTCAGTTAATCGTG GGGGCCAAGAGTGAG TCCTTCCATTCCCTT CTCAGTTAATCGTGA GGGCCAAGAGTGAGA CCTTCCATTCCCTTG TCAGTTAATCGTGAA CAGTTAATCGTGAAG CCTGAGTTACTACAT GCTACCTTTACCGGC AGTTAATCGTGAAGT CTGAGTTACTACATT CTACCTTTACCGGCA GTTAATCGTGAAGTG TGAGTTACTACATTG TACCTTTACCGGCAC TTAATCGTGAAGTGG GAGTTACTACATTGT ACCTTTACCGGCACA TAATCGTGAAGTGGA AGTTACTACATTGTG CCTTTACCGGCACAA AATCGTGAAGTGGAA GTTACTACATTGTGC CTTTACCGGCACAAT ATCGTGAAGTGGAAC TTACTACATTGTGCG TTTACCGGCACAATT TCGTGAAGTGGAACC TACTACATTGTGCGC TTACCGGCACAATTA CGTGAAGTGGAACCC ACTACATTGTGCGCT TACCGGCACAATTAC GTGAAGTGGAACCCT CTACATTGTGCGCTG ACCGGCACAATTACT TGAAGTGGAACCCTC TACATTGTGCGCTGG CCGGCACAATTACTG GAAGTGGAACCCTCC ACATTGTGCGCTGGC CGGCACAATTACTGC AAGTGGAACCCTCCC CATTGTGCGCTGGCA GGCACAATTACTGCT AGTGGAACCCTCCCT ATTGTGCGCTGGCAG GCACAATTACTGCTC GTGGAACCCTCCCTC TTGTGCGCTGGCAGC CACAATTACTGCTCC TGGAACCCTCCCTCT TGTGCGCTGGCAGCG ACAATTACTGCTCCA GGAACCCTCCCTCTC GTGCGCTGGCAGCGG CAATTACTGCTCCAA GAACCCTCCCTCTCT TGCGCTGGCAGCGGC AATTACTGCTCCAAA AACCCTCCCTCTCTG GCGCTGGCAGCGGCA ATTACTGCTCCAAAG ACCCTCCCTCTCTGC CGCTGGCAGCGGCAG TTACTGCTCCAAAGA CCCTCCCTCTCTGCC GCTGGCAGCGGCAGC TACTGCTCCAAAGAC CCTCCCTCTCTGCCC CTGGCAGCGGCAGCC ACTGCTCCAAAGACA CTCCCTCTCTGCCCA TGGCAGCGGCAGCCT CTGCTCCAAAGACAA TCCCTCTCTGCCCAA GGCAGCGGCAGCCTC TGCTCCAAAGACAAA CCCTCTCTGCCCAAC GCAGCGGCAGCCTCA GCTCCAAAGACAAAA CCTCTCTGCCCAACG CAGCGGCAGCCTCAG CTCCAAAGACAAAAT CTCTCTGCCCAACGG AGCGGCAGCCTCAGG TCCAAAGACAAAATC TCTCTGCCCAACGGC GCGGCAGCCTCAGGA CCAAAGACAAAATCC CTCTGCCCAACGGCA CGGCAGCCTCAGGAC CAAAGACAAAATCCC TCTGCCCAACGGCAA GGCAGCCTCAGGACG AAAGACAAAATCCCC CTGCCCAACGGCAAC GCAGCCTCAGGACGG AAGACAAAATCCCCA TGCCCAACGGCAACC CAGCCTCAGGACGGC AGACAAAATCCCCAT GCCCAACGGCAACCT AGCCTCAGGACGGCT GACAAAATCCCCATC CCCAACGGCAACCTG GCCTCAGGACGGCTA ACAAAATCCCCATCA CCAACGGCAACCTGA CCTCAGGACGGCTAC CAAAATCCCCATCAG CAACGGCAACCTGAG CTCAGGACGGCTACC AAAATCCCCATCAGG AACGGCAACCTGAGT TCAGGACGGCTACCT AAATCCCCATCAGGA ACGGCAACCTGAGTT CAGGACGGCTACCTT AATCCCCATCAGGAA CGGCAACCTGAGTTA AGGACGGCTACCTTT ATCCCCATCAGGAAG GGCAACCTGAGTTAC GGACGGCTACCTTTA TCCCCATCAGGAAGT GCAACCTGAGTTACT GACGGCTACCTTTAC CCCCATCAGGAAGTA CAACCTGAGTTACTA ACGGCTACCTTTACC CCCATCAGGAAGTAT AACCTGAGTTACTAC CGGCTACCTTTACCG CCATCAGGAAGTATG ACCTGAGTTACTACA GGCTACCTTTACCGG CATCAGGAAGTATGC ATCAGGAAGTATGCC AGAGAACCCCAAGAC GCTGCGCCTGCCCCA TCAGGAAGTATGCCG GAGAACCCCAAGACT CTGCGCCTGCCCCAA CAGGAAGTATGCCGA AGAACCCCAAGACTG TGCGCCTGCCCCAAA AGGAAGTATGCCGAC GAACCCCAAGACTGA GCGCCTGCCCCAAAA GGAAGTATGCCGACG AACCCCAAGACTGAG CGCCTGCCCCAAAAC GAAGTATGCCGACGG ACCCCAAGACTGAGG GCCTGCCCCAAAACT AAGTATGCCGACGGC CCCCAAGACTGAGGT CCTGCCCCAAAACTG AGTATGCCGACGGCA CCCAAGACTGAGGTG CTGCCCCAAAACTGA GTATGCCGACGGCAC CCAAGACTGAGGTGT TGCCCCAAAACTGAA TATGCCGACGGCACC CAAGACTGAGGTGTG GCCCCAA.AACTGAAG ATGCCGACGGCACCA AAGACTGAGGTGTGT CCCCAAAACTGAAGC TGCCGACGGCACCAT AGACTGAGGTGTGTG CCCAAAACTGAAGCC GCCGACGGCACCATC GACTGAGGTGTGTGG CCAAAACTGAAGCCG CCGACGGCACCATCG ACTGAGGTGTGTGGT CAAAACTGAAGCCGA CGACGGCACCATCGA CTGAGGTGTGTGGTG AAAACTGAAGCCGAG GACGGCACCATCGAC TGAGGTGTGTGGTGG AAACTGAAGCCGAGA ACGGCACCATCGACA GAGGTGTGTGGTGGG AACTGAAGCCGAGAA CGGCACCATCGACAT AGGTGTGTGGTGGGG ACTGAAGCCGAGAAG GGCACCATCGACATT GGTGTGTGGTGGGGA CTGAAGCCGAGAAGC GCACCATCGACATTG GTGTGTGGTGGGGAG TGAAGCCGAGAAGCA CACCATCGACATTGA TGTGTGGTGGGGAGA GAAGCCGAGAAGCAG ACCATCGACATTGAG GTGTGGTGGGGAGAA AAGCCGAGAAGCAGG CCATCGACATTGAGG TGTGGTGGGGAGAAA AGCCGAGAAGCAGGC CATCGACATTGAGGA GTGGTGGGGAGAAAG GCCGAGAAGCAGGCC ATCGACATTGAGGAG TGGTGGGGAGAAAGG CCGAGAAGCAGGCCG TCGACATTGAGGAGG GGTGGGGAGAAAGGG CGAGAAGCAGGCCGA CGACATTGAGGAGGT GTGGGGAGAAAGGGC GAGAAGCAGGCCGAG GACATTGAGGAGGTC TGGGGAGAAAGGGCC AGAAGCAGGCCGAGA ACATTGAGGAGGTCA GGGGAGAAAGGGCCT GAAGCAGGCCGAGAA CATTGAGGAGGTCAC GGGAGAAAGGGCCTT AAGCAGGCCGAGAAG ATTGAGGAGGTCACA GGAGAAAGGGCCTTG AGCAGGCCGAGAAGG TTGAGGAGGTCACAG GAGAAAGGGCCTTGC GCAGGCCGAGAAGGA TGAGGAGGTCACAGA AGAAAGGGCCTTGCT CAGGCCGAGAAGGAG GAGGAGGTCACAGAG GAAAGGGCCTTGCTG AGGCCGAGAAGGAGG AGGAGGTCACAGAGA AAAGGGCCTTGCTGC GGCCGAGAAGGAGGA GGAGGTCACAGAGAA AAGGGCCTTGCTGCG GCCGAGAAGGAGGAG GAGGTCACAGAGAAC AGGGCCTTGCTGCGC CCGAGAAGGAGGAGG AGGTCACAGAGAACC GGGCCTTGCTGCGCC CGAGAAGGAGGAGGC GGTCACAGAGAACCC GGCCTTGCTGCGCCT GAGAAGGAGGAGGCT GTCACAGAGAACCCC GCCTTGCTGCGCCTG AGAAGGAGGAGGCTG TCACAGAGAACCCCA CCTTGCTGCGCCTGC GAAGGAGGAGGCTGA CACAGAGAACCCCAA CTTGCTGCGCCTGCC AAGGAGGAGGCTGAA ACAGAGAACCCCAAG TTGCTGCGCCTGCCC AGGAGGAGGCTGAAT CAGAGAACCCCAAGA TGCTGCGCCTGCCCC GGAGGAGGCTGAATA GAGGAGGCTGAATAC CTCCATCTTCGTGCC TGCAAGTGGCCAACA AGGAGGCTGAATACC TCCATCTTCGTGCCC GCAAGTGGCCAACAC GGAGGCTGAATACCG CCATCTTCGTGCCCA CAAGTGGCCAACACC GAGGCTGAATACCGC CATCTTCGTGCCCAG AAGTGGCCAACACCA AGGCTGAATACCGCA ATCTTCGTGCCCAGA AGTGGCCAACACCAC GGCTGAATACCGCAA TCTTCGTGCCCAGAC GTGGCCAACACCACC GCTGAATACCGCAAA CTTCGTGCCCAGACC TGGCCAACACCACCA CTGAATACCGCAAAG TTCGTGCCCAGACCT GGCCAACACCACCAT TGAATACCGCAAAGT TCGTGCCCAGACCTG GCCAACACCACCATG GAATACCGCAAAGTC CGTGCCCAGACCTGA CCAACACCACCATGT AATACCGCAAAGTCT GTGCCCAGACCTCAA CAACACCACCATGTC ATACCGCAAAGTCTT TGCCCAGACCTGAAA AACACCACCATGTCC TACCGCAAAGTCTTT GCCCAGACCTGAAAG ACACCACCATGTCCA ACCGCAAAGTCTTTG CCCAGACCTGAAAGG CACCACCATGTCCAG CCGCAAAGTCTTTGA CCAGACCTGAAAGGA ACCACCATGTCCAGC CGCAAAGTCTTTGAG CAGACCTGAAAGGAA CCACCATGTCCAGCC GCAAAGTCTTTGAGA AGACCTGAAAGGAAG CACCATGTCCAGCCG CAAAGTCTTTGAGAA GACCTGAAAGGAAGC ACCATGTCCAGCCGA AAAGTCTTTGAGAAT ACCTGAAAGGAAGCG CCATGTCCAGCCGAA AAGTCTTTGAGAATT CCTGAAAGGAAGCGG CATGTCCAGCCGAAG AGTCTTTGAGAATTT CTGAAAGGAAGCGGA ATGTCCAGCCGAAGC GTCTTTGAGAATTTC TGAAAGGAAGCGGAG TGTCCAGCCGAAGCA TCTTTGAGAATTTCC GAAAGGAAGCGGAGA GTCCAGCCGAAGCAG CTTTGAGAATTTCCT AAAGGAAGCGGAGAG TCCAGCCGAAGCAGG TTTGAGAATTTCCTG AAGGAAGCGGAGAGA CCAGCCGAAGCAGGA TTGAGAATTTCCTGC AGGAAGCGGAGAGAT CAGCCGAAGCAGGAA TGAGAATTTCCTGCA GGAAGCGGAGAGATG AGCCGAAGCAGGAAC GAGAATTTCCTGCAC GAAGCGGAGAGATGT GCCGAAGCAGGAACA AGAATTTCCTGCACA AAGCGGAGAGATGTC CCGAAGCAGGAACAC GAATTTCCTGCACAA AGCGGAGAGATGTCA CGAAGCAGGAACACC AATTTCCTGCACAAC GCGGAGAGATGTCAT GAAGCAGGAACACCA ATTTCCTGCACAACT CGGAGAGATGTCATG AAGCAGGAACACCAC TTTCCTGCACAACTC GGAGAGATGTCATGC AGCAGGAACACCACG TTCCTGCACAACTCC GAGAGATGTCATGCA GCAGGAACACCACGG TCCTGCACAACTCCA AGAGATGTCATGCAA CAGGAACACCACGGC CCTGCACAACTCCAT GAGATGTCATGCAAG AGGAACACCACGGCC CTGCACAACTCCATC AGATGTCATGCAAGT GGAACACCACGGCCG TGCACAACTCCATCT GATGTCATGCAAGTG GAACACCACGGCCGC GCACAACTCCATCTT ATGTCATGCAAGTGG AACACCACGGCCGCA CACAACTCCATCTTC TGTCATGCAAGTGGC ACACCACGGCCGCAG ACAACTCCATCTTCG GTCATGCAAGTGGCC CACCACGGCCGCAGA CAACTCCATCTTCGT TCATGCAAGTGGCCA ACCACGGCCGCAGAC AACTCCATCTTCGTG CATGCAAGTGGCCAA CCACGGCCGCAGACA ACTCCATCTTCGTGC ATGCAAGTGGCCAAC CACGGCCGCAGACAC ACGGCCGCAGACACC GACAGAGTACCCTTT GAACTGTCATTTCTA CGGCCGCAGACACCT ACAGAGTACCCTTTC AACTGTCATTTCTAA GGCCGCAGACACCTA CAGAGTACCCTTTCT ACTGTCATTTCTAAC GCCGCAGACACCTAC AGAGTACCCTTTCTT CTGTCATTTCTAACC CCGCAGACACCTACA GAGTACCCTTTCTTT TGTCATTTCTAACCT CGCAGACACCTACAA AGTACCCTTTCTTTG GTCATTTCTAACCTT GCAGACACCTACAAC GTACCCTTTCTTTGA TCATTTCTAACCTTC CAGACACCTACAACA TACCCTTTCTTTGAG CATTTCTAACCTTCG AGACACCTACAACAT ACCCTTTCTTTGAGA ATTTCTAACCTTCGG GACACCTACAACATC CCCTTTCTTTGAGAG TTTCTAACCTTCGGC ACACCTACAACATCA CCTTTCTTTGAGAGC TTCTAACCTTCGGCC CACCTACAACATCAC CTTTCTTTGAGAGCA TCTAACCTTCGGCCT ACCTACAACATCACC TTTCTTTGAGAGCAG CTAACCTTCGGCCTT CCTACAACATCACCG TTCTTTGAGAGCAGA TAACCTTCGGCCTTT CTACAACATCACCGA TCTTTGAGAGCAGAG AACCTTCGGCCTTTC TACAACATCACCGAC CTTTGAGAGCAGAGT ACCTTCGGCCTTTCA ACAACATCACCGACC TTTGAGAGCAGAGTG CCTTCGGCCTTTCAC CAACATCACCGACCC TTGAGAGCAGAGTGG CTTCGGCCTTTCACA AACATCACCGACCCG TGAGAGCAGAGTGGA TTCGGCCTTTCACAT ACATCACCGACCCGG GAGAGCAGAGTGGAT TCGGCCTTTCACATT CATCACCGACCCGGA AGAGCAGAGTGGATA CGGCCTTTCACATTG ATCACCGACCCGGAA GAGCAGAGTGGATAA GGCCTTTCACATTGT TCACCGACCCGGAAG AGCAGAGTGGATAAC GCCTTTCACATTGTA CACCGACCCGGAAGA GCAGAGTGGATAACA CCTTTCACATTGTAC ACCGACCCGGAAGAG CAGAGTGGATAACAA CTTTCACATTGTACC CCGACCCGGAAGAGC AGAGTGGATAACAAG TTTCACATTGTACCG CGACCCGGAAGAGCT GAGTGGATAACAAGG TTCACATTGTACCGC GACCCGGAAGAGCTG AGTGGATAACAAGGA TCACATTGTACCGCA ACCCGGAAGAGCTGG GTGGATAACAAGGAG CACATTGTACCGCAT CCCGGAAGAGCTGGA TGGATAACAAGGAGA ACATTGTACCGCATC CCGGAAGAGCTGGAG GGATAACAAGGAGAG CATTGTACCGCATCG CGGAAGAGCTGGAGA GATAACAAGGAGAGA ATTGTACCGCATCGA GGAAGAGCTGGAGAC ATAACAAGGAGAGAA TTGTACCGCATCGAT GAAGAGCTGGAGACA TAACAAGGAGAGAAC TGTACCGCATCGATA AAGAGCTGGAGACAG AACAAGGAGAGAACT GTACCGCATCGATAT AGAGCTGGAGACAGA ACAAGGAGAGAACTG TACCGCATCGATATC GAGCTGGAGACAGAG CAAGGAGAGAACTGT ACCGCATCGATATCC AGCTGGAGACAGAGT AAGGAGAGAACTGTC CCGCATCGATATCCA GCTGGAGACAGAGTA AGGAGAGAACTGTCA CGCATCGATATCCAC CTGGAGACAGAGTAC GGAGAGAACTGTCAT GCATCGATATCCACA TGGAGACAGAGTACC GAGAGAACTGTCATT CATCGATATCCACAG GGAGACAGAGTACCC AGAGAACTGTCATTT ATCGATATCCACAGC GAGACAGAGTACCCT GAGAACTGTCATTTC TCGATATCCACAGCT AGACAGAGTACCCTT AGAACTGTCATTTCT CGATATCCACAGCTG GATATCCACAGCTGC CGCCTCCAACTTCGT CAGATGACATTCCTG ATATCCACAGCTGCA GCCTCCAACTTCGTC AGATGACATTCCTGG TATCCACAGCTGCAA CCTCCAACTTCGTCT GATGACATTCCTGGG ATCCACAGCTGCAAC CTCCAACTTCGTCTT ATGACATTCCTGGGC TCCACAGCTGCAACC TCCAACTTCGTCTTT TGACATTCCTGGGCC CCACAGCTGCAACCA CCAACTTCGTCTTTG GACATTCCTGGGCCA CACAGCTGCAACCAC CAACTTCGTCTTTGC ACATTCCTGGGCCAG ACAGCTGCAACCACG AACTTCGTCTTTGCA CATTCCTGGGCCAGT CAGCTGCAACCACGA ACTTCGTCTTTGCAA ATTCCTGGGCCAGTG AGCTGCAACCACGAG CTTCGTCTTTGCAAG TTCCTGGGCCAGTGA GCTGCAACCACGAGG TTCGTCTTTGCAAGG TCCTGGGCCAGTGAC CTGCAACCACGAGGC TCGTCTTTGCAAGGA CCTGGGCCAGTGACC TGCAACCACGAGGCT CGTCTTTGCAAGGAC CTGGGCCAGTGACCT GCAACCACGAGGCTG GTCTTTGCAAGGACT TGGGCCAGTGACCTG CAACCACGAGGCTGA TCTTTGCAAGGACTA GGGCCAGTGACCTGG AACCACGAGGCTGAG CTTTGCAAGGACTAT GGCCAGTGACCTGGG ACCACGAGGCTGAGA TTTGCAAGGACTATG GCCAGTGACCTGGGA CCACGAGGCTGAGAA TTGCAAGGACTATGC CCAGTGACCTGGGAG CACGAGGCTGAGAAG TGCAAGGACTATGCC CAGTGACCTGGGAGC ACGAGGCTGAGAAGC GCAAGGACTATGCCC AGTGACCTGGGAGCC CGAGGCTGAGAAGCT CAAGGACTATGCCCG GTGACCTGGGAGCCA GAGGCTGAGAAGCTG AAGGACTATGCCCGC TGACCTGGGAGCCAA AGGCTGAGAAGCTGG AGGACTATGCCCGCA GACCTGGGAGCCAAG GGCTGAGAAGCTGGG GGACTATGCCCGCAG ACCTGGGAGCCAAGG GCTGAGAAGCTGGGC GACTATGCCCGCAGA CCTGGGAGCCAAGGC CTGAGAAGCTGGGCT ACTATGCCCGCAGAA CTGGGAGCCAAGGCC TGAGAAGCTGGGCTG CTATGCCCGCAGAAG TGGGAGCCAAGGCCT GAGAAGCTGGGCTGC TATGCCCGCAGAAGG GGGAGCCAAGGCCTG AGAAGCTGGGCTGCA ATGCCCGCAGAAGGA GGAGCCAAGGCCTGA GAAGCTGGGCTGCAG TGCCCGCAGAAGGAG GAGCCAAGGCCTGAA AAGCTGGGCTGCAGC GCCCGCAGAAGGAGC AGCCAAGGCCTGAAA AGCTGGGCTGCAGCG CCCGCAGAAGGAGCA GCCAAGGCCTGAAAA GCTGGGCTGCAGCGC CCGCAGAAGGAGCAG CCAAGGCCTGAAAAC CTGGGCTGCAGCGCC CGCAGAAGGAGCAGA CAAGGCCTGAAAACT TGGGCTGCAGCGCCT GCAGAAGGAGCAGAT AAGGCCTGAAAACTC GGGCTGCAGCGCCTC CAGAAGGAGCAGATG AGGCCTGAAAACTCC GGCTGCAGCGCCTCC AGAAGGAGCAGATGA GGCCTGAAAACTCCA GCTGCAGCGCCTCCA GAAGGAGCAGATGAC GCCTGAAAACTCCAT CTGCAGCGCCTCCAA AAGGAGCAGATGACA CCTGAAAACTCCATC TGCAGCGCCTCCAAC AGGAGCAGATGACAT CTGAAAACTCCATCT GCAGCGCCTCCAACT GGAGCAGATGACATT TGAAAACTCCATCTT CAGCGCCTCCAACTT GAGCAGATGACATTC GAAAACTCCATCTTT AGCGCCTCCAACTTC AGCAGATGACATTCC AAAACTCCATCTTTT GCGCCTCCAACTTCG GCAGATGACATTCCT AAACTCCATCTTTTT AACTCCATCTTTTTA ATTGATTCTAATGTA ATCAGCGAGAATGTG ACTCCATCTTTTTAA TTGATTCTAATGTAT TCAGCGAGAATGTGT CTCCATCTTTTTAAA TGATTCTAATGTATG CAGCGAGAATGTGTG TCCATCTTTTTAAAG GATTCTAATGTATGA AGCGAGAATGTGTGT CCATCTTTTTAAAGT ATTCTAATGTATGAA GCGAGAATGTGTGTC CATCTTTTTAAAGTG TTCTAATGTATGAAA CGAGAATGTGTGTCC ATCTTTTTAAAGTGG TCTAATGTATGAAAT GAGAATGTGTGTCCA TCTTTTTAAAGTGGC CTAATGTATGAAATA AGAATGTGTGTCCAG CTTTTTAAAGTGGCC TAATGTATGAAATAA GAATGTGTGTCCAGA TTTTTAAAGTGGCCG AATGTATGAAATAAA AATGTGTGTCCAGAC TTTTAAAGTGGCCGG ATGTATGAAATAAAA ATGTGTGTCCAGACA TTTAAAGTGGCCGGA TGTATGAAATAAAAT TGTGTGTCCAGACAG TTAAAGTGGCCGGAA GTATGAAATAAAATA GTGTGTCCAGACAGG TAAAGTGGCCGGAAC TATGAAATAAAATAC TGTGTCCAGACAGGA AAAGTGGCCGGAACC ATGAAATAAAATACG GTGTCCAGACAGGAA AAGTGGCCGGAACCT TGAAATAAAATACGG TGTCCAGACAGGAAT AGTGGCCGGAACCTG GAAATAAAATACGGA GTCCAGACAGGAATA GTGGCCGGAACCTGA AAATAAAATACGGAT TCCAGACAGGAATAC TGGCCGGAACCTGAG AATAAAATACGGATC CCAGACAGGAATACA GGCCGGAACCTGAGA ATAAAATACGGATCA CAGACAGGAATACAG GCCGGAACCTGAGAA TAAAATACGGATCAC AGACAGGAATACAGG CCGGAACCTGAGAAT AAAATACGGATCACA GACAGGAATACAGGA CGGAACCTGAGAATC AAATACGGATCACAA ACAGGAATACAGGAA GGAACCTGAGAATCC AATACGGATCACAAG CAGGAATACAGGAAG GAACCTGAGAATCCC ATACGGATCACAAGT AGGAATACAGGAAGT AACCTGAGAATCCCA TACGGATCACAAGTT GGAATACAGGAAGTA ACCTGAGAATCCCAA ACGGATCACAAGTTG GAATACAGGAAGTAT CCTGAGAATCCCAAT CGGATCACAAGTTGA AATACAGGAAGTATG CTGAGAATCCCAATG GGATCACAAGTTGAG ATACAGGAAGTATGG TGAGAATCCCAATGG GATCACAAGTTGAGG TACAGGAAGTATGGA GAGAATCCCAATGGA ATCACAAGTTGAGGA ACAGGAAGTATGGAG AGAATCCCAATGGAT TCACAAGTTGAGGAT CAGGAAGTATGGAGG GAATCCCAATGGATT CACAAGTTGAGGATC AGGAAGTATGGAGGG AATCCCAATGGATTG ACAAGTTGAGGATCA GGAAGTATGGAGGGG ATCCCAATGGATTGA CAAGTTGAGGATCAG GAAGTATGGAGGGGC TCCCAATGGATTGAT AAGTTGAGGATCAGC AAGTATGGAGGGGCC CCCAATGGATTGATT AGTTGAGGATCAGCG AGTATGGAGGGGCCA CCAATGGATTGATTC GTTGAGGATCAGCGA GTATGGAGGGGCCAA CAATGGATTGATTCT TTGAGGATCAGCGAG TATGGAGGGGCCAAG AATGGATTGATTCTA TGAGGATCAGCGAGA ATGGAGGGGCCAAGC ATGGATTGATTCTAA GAGGATCAGCGAGAA TGGAGGGGCCAAGCT TGGATTGATTCTAAT AGGATCAGCGAGAAT GGAGGGGCCAAGCTA GGATTGATTCTAATG GGATCAGCGAGAATG GAGGGGCCAAGCTAA GATTGATTCTAATGT GATCAGCGAGAATGT AGGGGCCAAGCTAAA GGGGCCAAGCTAAAC GATTCAGGCCACATC CTGTGTTCTTCTATG GGGCCAAGCTAAACC ATTCAGGCCACATCT TGTGTTCTTCTATGT GGCCAAGCTAAACCG TTCAGGCCACATCTC GTGTTCTTCTATGTC GCCAAGCTAAACCGG TCAGGCCACATCTCT TGTTCTTCTATGTCC CCAAGCTAAACCGGC CAGGCCACATCTCTC GTTCTTCTATGTCCA CAAGCTAAACCGGCT AGGCCACATCTCTCT TTCTTCTATGTCCAG AAGCTAAACCGGCTA GGCCACATCTCTCTC TCTTCTATGTCCAGG AGCTAAACCGGCTAA GCCACATCTCTCTCT CTTCTATGTCCAGGC GCTAAACCGGCTAAA CCACATCTCTCTCTG TTCTATGTCCAGGCC CTAAACCGGCTAAAC CACATCTCTCTCTGG TCTATGTCCAGGCCA TAAACCGGCTAAACC ACATCTCTCTCTGGG CTATGTCCAGGCCAA AAACCGGCTAAACCC CATCTCTCTCTGGGA TATGTCCAGGCCAAA AACCGGCTAAACCCG ATCTCTCTCTGGGAA ATGTCCAGGCCAAAA ACCGGCTAAACCCGG TCTCTCTCTGGGAAT TGTCCAGGCCAAAAC CCGGCTAAACCCGGG CTCTCTCTGGGAATG GTCCAGGCCAAAACA CGGCTAAACCCGGGG TCTCTCTGGGAATGG TCCAGGCCAAAACAG GGCTAAACCCGGGGA CTCTCTGGGAATGGG CCAGGCCAAAACAGG GCTAAACCCGGGGAA TCTCTGGGAATGGGT CAGGCCAAAACAGGA CTAAACCCGGGGAAC CTCTGGGAATGGGTC AGGCCAAAACAGGAT TAAACCCGGGGAACT TCTGGGAATGGGTCG GGCCAAAACAGGATA AAACCCGGGGAACTA CTGGGAATGGGTCGT GCCAAAACAGGATAT AACCCGGGGAACTAC TGGGAATGGGTCGTG CCAAAACAGGATATG ACCCGGGGAACTACA GGGAATGGGTCGTGG CAAAACAGGATATGA CCCGGGGAACTACAC GGAATGGGTCGTGGA AAAACAGGATATGAA CCGGGGAACTACACA GAATGGGTCGTGGAC AAACAGGATATGAAA CGGGGAACTACACAG AATGGGTCGTGGACA AACAGGATATGAAAA GGGGAACTACACAGC ATGGGTCGTGGACAG ACAGGATATGAAAAC GGGAACTACACAGCC TGGGTCGTGGACAGA CAGGATATGAAAACT GGAACTACACAGCCC GGGTCGTGGACAGAT AGGATATGAAAACTT GAACTACACAGCCCG GGTCGTGGACAGATC GGATATGAAAACTTC AACTACACAGCCCGG GTCGTGGACAGATCC GATATGAAAACTTCA ACTACACAGCCCGGA TCGTGGACAGATCCT ATATGAAAACTTCAT CTACACAGCCCGGAT CGTGGACAGATCCTG TATGAAAACTTCATC TACACAGCCCGGATT GTGGACAGATCCTGT ATGAAAACTTCATCC ACACAGCCCGGATTC TGGACAGATCCTGTG TGAAAACTTCATCCA CACAGCCCGGATTCA GGACAGATCCTGTGT GAAAACTTCATCCAT ACAGCCCGGATTCAG GACAGATCCTGTGTT AAAACTTCATCCATC CAGCCCGGATTCAGG ACAGATCCTGTGTTC AAACTTCATCCATCT AGCCCGGATTCAGGC CAGATCCTGTGTTCT AACTTCATCCATCTG GCCCGGATTCAGGCC AGATCCTGTGTTCTT ACTTCATCCATCTGA CCCGGATTCAGGCCA GATCCTGTGTTCTTC CTTCATCCATCTGAT CCGGATTCAGGCCAC ATCCTGTGTTCTTCT TTCATCCATCTGATC CGGATTCAGGCCACA TCCTGTGTTCTTCTA TCATCCATCTGATCA GGATTCAGGCCACAT CCTGTGTTCTTCTAT CATCCATCTGATCAT ATCCATCTGATCATC GGGAGGGTTGGTGAT ATAACAGCAGGCTGG TCCATCTGATCATCG GGAGGGTTGGTGATT TAACAGCAGGCTGGG CCATCTGATCATCGC GAGGGTTGGTGATTA AACAGCAGGCTGGGG CATCTGATCATCGCT AGGGTTGGTGATTAT ACAGCAGGCTGGGGA ATCTGATCATCGCTC GGGTTGGTGATTATG CAGCAGGCTGGGGAA TCTGATCATCGCTCT GGTTGGTGATTATGC AGCAGGCTGGGGAAT CTGATCATCGCTCTG GTTGGTGATTATGCT GCAGGCTGGGGAATG TGATCATCGCTCTGC TTGGTGATTATGCTG CAGGCTGGGGAATGG GATCATCGCTCTGCC TGGTGATTATGCTGT AGGCTGGGGAATGGA ATCATCGCTCTGCCC GGTGATTATGCTGTA GGCTGGGGAATGGAG TCATCGCTCTGCCCG GTGATTATGCTGTAC GCTGGGGAATGGAGT CATCGCTCTGCCCGT TGATTATGCTGTACG CTGGGGAATGGAGTG ATCGCTCTGCCCGTC GATTATGCTGTACGT TGGGGAATGGAGTGC TCGCTCTGCCCGTCG ATTATGCTGTACGTC GGGGAATGGAGTGCT CGCTCTGCCCGTCGC TTATGCTGTACGTCT GGGAATGGAGTGCTG GCTCTGCCCGTCGCT TATGCTGTACGTCTT GGAATGGAGTGCTGT CTCTGCCCGTCGCTG ATGCTGTACGTCTTC GAATGGAGTGCTGTA TCTGCCCGTCGCTGT TGCTGTACGTCTTCC AATGGAGTGCTGTAT CTGCCCGTCGCTGTC GCTGTACGTCTTCCA ATGGAGTGCTGTATG TGCCCGTCGCTGTCC CTGTACGTCTTCCAT TGGAGTGCTGTATGC GCCCGTCGCTGTCCT TGTACGTCTTCCATA GGAGTGCTGTATGCC CCCGTCGCTGTCCTG GTACGTCTTCCATAG GAGTGCTGTATGCCT CCGTCGCTGTCCTGT TACGTCTTCCATAGA AGTGCTGTATGCCTC CGTCGCTGTCCTGTT ACGTCTTCCATAGAA GTGCTGTATGCCTCT GTCGCTGTCCTGTTG CGTCTTCCATAGAAA TGCTGTATGCCTCTG TCGCTGTCCTGTTGA GTCTTCCATAGAAAG GCTGTATGCCTCTGT CGCTGTCCTGTTGAT TCTTCCATAGAPAGA CTGTATGCCTCTGTG GCTGTCCTGTTGATC CTTCCATAGAAAGAG TGTATGCCTCTGTGA CTGTCCTGTTGATCG TTCCATAGAAAGAGA GTATGCCTCTGTGAA TGTCCTGTTGATCGT TCCATAGAAAGAGAA TATGCCTCTGTGAAC GTCCTGTTGATCGTG CCATAGAAAGAGAAA ATGCCTCTGTGAACC TCCTGTTGATCGTGG CATAGAAAGAGAAAT TGCCTCTGTGAACCC CCTGTTGATCGTGGG ATAGAAAGAGAAATA GCCTCTGTGAACCCG CTGTTGATCGTGGGA TAGAAAGAGAAATAA CCTCTGTGAACCCGG TGTTGATCGTGGGAG AGAAAGAGPAATAAC CTCTGTGAACCCGGA GTTGATCGTGGGAGG GAAAGAGAAATAACA TCTGTGAACCCGGAG TTGATCGTGGGAGGG AAAGAGAAATAACAG CTGTGAACCCGGAGT TGATCGTGGGAGGGT AAGAGAAATAACAGC TGTGAACCCGGAGTA GATCGTGGGAGGGTT AGAGAAATAACAGCA GTGAACCCGGAGTAC ATCGTGGGAGGGTTG GAGAAATAACAGCAG TGAACCCGGAGTACT TCGTGGGAGGGTTGG AGAAATAACAGCAGG GAACCCGGAGTACTT CGTGGGAGGGTTGGT GAAATAACAGCAGGC AACCCGGAGTACTTC GTGGGAGGGTTGGTG AAATAACAGCAGGCT ACCCGGAGTACTTCA TGGGAGGGTTGGTGA AATAACAGCAGGCTG CCCGGAGTACTTCAG CCGGAGTACTTCAGC GGAGGTGGCTCGGGA AGGGGTCGTTTGGGA CGGAGTACTTCAGCG GAGGTGGCTCGGGAG GGGGTCGTTTGGGAT GGAGTACTTCAGCGC AGGTGGCTCGGGAGA GGGTCGTTTGGGATG GAGTACTTCAGCGCT GGTGGCTCGGGAGAA GGTCGTTTGGGATGG AGTACTTCAGCGCTG GTGGCTCGGGAGAAG GTCGTTTGGGATGGT GTACTTCAGCGCTGC TGGCTCGGGAGAAGA TCGTTTGGGATGGTC TACTTCAGCGCTGCT GGCTCGGGAGAAGAT CGTTTGGGATGGTCT ACTTCAGCGCTGCTG GCTCGGGAGAAGATC GTTTGGGATGGTCTA CTTCAGCGCTGCTGA CTCGGGAGAAGATCA TTTGGGATGGTCTAT TTCAGCGCTGCTGAT TCGGGAGAAGATCAC TTGGGATGGTCTATG TCAGCGCTGCTGATG CGGGAGAAGATCACC TGGGATGGTCTATGA CAGCGCTGCTGATGT GGGAGAAGATCACCA GGGATGGTCTATGAA AGCGCTGCTGATGTG GGAGAAGATCACCAT GGATGGTCTATGAAG GCGCTGCTGATGTGT GAGAAGATCACCATG GATGGTCTATGAAGG CGCTGCTGATGTGTA AGAAGATCACCATGA ATGGTCTATGAAGGA GCTGCTGATGTGTAC GAAGATCACCATGAG TGGTCTATGAAGGAG CTGCTGATGTGTACG AAGATCACCATGAGC GGTCTATGAAGGAGT TGCTGATGTGTACGT AGATCACCATGAGCC GTCTATGAAGGAGTT GCTGATGTGTACGTT GATCACCATGAGCCG TCTATGAAGGAGTTG CTGATGTGTACGTTC ATCACCATGAGCCGG CTATGAAGGAGTTGC TGATGTGTACGTTCC TCACCATGAGCCGGG TATGAAGGAGTTGCC GATGTGTACGTTCCT CACCATGAGCCGGGA ATGAAGGAGTTGCCA ATGTGTACGTTCCTG ACCATGAGCCGGGAA TGAAGGAGTTGCCAA TGTGTACGTTCCTGA CCATGAGCCGGGAAC GAAGGAGTTGCCAAG GTGTACGTTCCTGAT CATGAGCCGGGAACT AAGGAGTTGCCAAGG TGTACGTTCCTGATG ATGAGCCGGGAACTT AGGAGTTGCCAAGGG GTACGTTCCTGATGA TGAGCCGGGAACTTG GGAGTTGCCAAGGGT TACGTTCCTGATGAG GAGCCGGGAACTTGG GAGTTGCCAAGGGTG ACGTTCCTGATGAGT AGCCGGGAACTTGGG AGTTGCCAAGGGTGT CGTTCCTGATGAGTG GCCGGGAACTTGGGC GTTGCCAAGGGTGTG GTTCCTGATGAGTGG CCGGGAACTTGGGCA TTGCCAAGGGTGTGG TTCCTGATGAGTGGG CGGGAACTTGGGCAG TGCCAAGGGTGTGGT TCCTGATGAGTGGGA GGGAACTTGGGCAGG GCCAAGGGTGTGGTG CCTGATGAGTGGGAG GGAACTTGGGCAGGG CCAAGGGTGTGGTGA CTGATGAGTGGGAGG GAACTTGGGCAGGGG CAAGGGTGTGGTGAA TGATGAGTGGGAGGT AACTTGGGCAGGGGT AAGGGTGTGGTGAAA GATGAGTGGGAGGTG ACTTGGGCAGGGGTC AGGGTGTGGTGAAAG ATGAGTGGGAGGTGG CTTGGGCAGGGGTCG GGGTGTGGTGAAAGA TGAGTGGGAGGTGGC TTGGGCAGGGGTCGT GGTGTGGTGAAAGAT GAGTGGGAGGTGGCT TGGGCAGGGGTCGTT GTGTGGTGAAAGATG AGTGGGAGGTGGCTC GGGCAGGGGTCGTTT TGTGGTGAAAGATGA GTGGGAGGTGGCTCG GGCAGGGGTCGTTTG GTGGTGAAAGATGAA TGGGAGGTGGCTCGG GCAGGGGTCGTTTGG TGGTGAAAGATGAAC GGGAGGTGGCTCGGG CAGGGGTCGTTTGGG GGTGAAAGATGAACC GTGAAAGATGAACCT CGAGGCCGCAAGCAT CTTCTGTGATGAAGG TGAAAGATGAACCTG GAGGCCGCAAGCATG TTCTGTGATGAAGGA GAAAGATGAACCTGA AGGCCGCAAGCATGC TCTGTGATGAAGGAG AAAGATGAACCTGAA GGCCGCAAGCATGCG CTGTGATGAAGGAGT AAGATGAACCTGAAA GCCGCAAGCATGCGT TGTGATGAAGGAGTT AGATGAACCTGAAAC CCGCAAGCATGCGTG GTGATGAAGGAGTTC GATGAACCTGAAACC CGCAAGCATGCGTGA TGATGAAGGAGTTCA ATGAACCTGAAACCA GCAAGCATGCGTGAG GATGAAGGAGTTCAA TGAACCTGAAACCAG CAAGCATGCGTGAGA ATGAAGGAGTTCAAT GAACCTGAAACCAGA AAGCATGCGTGAGAG TGAAGGAGTTCAATT AACCTGAAACCAGAG AGCATGCGTGAGAGG GAAGGAGTTCAATTG ACCTGAAACCAGAGT GCATGCGTGAGAGGA AAGGAGTTCAATTGT CCTGAAACCAGAGTG CATGCGTGAGAGGAT AGGAGTTCAATTGTC CTGAAACCAGAGTGG ATGCGTGAGAGGATT GGAGTTCAATTGTCA TGAAACCAGAGTGGC TGCGTGAGAGGATTG GAGTTCAATTGTCAC GAAACCAGAGTGGCC GCGTGAGAGGATTGA AGTTCAATTGTCACC AAACCAGAGTGGCCA CGTGAGAGGATTGAG GTTCAATTGTCACCA AACCAGAGTGGCCAT GTGAGAGGATTGAGT TTCAATTGTCACCAT ACCAGAGTGGCCATT TGAGAGGATTGAGTT TCAATTGTCACCATG CCAGAGTGGCCATTA GAGAGGATTGAGTTT CAATTGTCACCATGT CAGAGTGGCCATTAA AGAGGATTGAGTTTC AATTGTCACCATGTG AGAGTGGCCATTAAA GAGGATTGAGTTTCT ATTGTCACCATGTGG GAGTGGCCATTAAAA AGGATTGAGTTTCTC TTGTCACCATGTGGT AGTGGCCATTAAAAC GGATTGAGTTTCTCA TGTCACCATGTGGTG GTGGCCATTAAAACA GATTGAGTTTCTCAA GTCACCATGTGGTGC TGGCCATTAAAACAG ATTGAGTTTCTCAAC TCACCATGTGGTGCG GGCCATTAAAACAGT TTGAGTTTCTCAACG CACCATGTGGTGCGA GCCATTAAAACAGTG TGAGTTTCTCAACGA ACCATGTGGTGCGAT CCATTAAAACAGTGA GAGTTTCTCAACGAA CCATGTGGTGCGATT CATTAAAACAGTGAA AGTTTCTCAACGAAG CATGTGGTGCGATTG ATTAAAACAGTGAAC GTTTCTCAACGAAGC ATGTGGTGCGATTGC TTAAAACAGTGAACG TTTCTCAACGAAGCT TGTGGTGCGATTGCT TAAAACAGTGAACGA TTCTCAACGAAGCTT GTGGTGCGATTGCTG AAAACAGTGAACGAG TCTCAACGAAGCTTC TGGTGCGATTGCTGG AAACAGTGAACGAGG CTCAACGAAGCTTCT GGTGCGATTGCTGGG AACAGTGAACGAGGC TCAACGAAGCTTCTG GTGCGATTGCTGGGT ACAGTGAACGAGGCC CAACGAAGCTTCTGT TGCGATTGCTGGGTG CAGTGAACGAGGCCG AACGAAGCTTCTGTG GCGATTGCTGGGTGT AGTGAACGAGGCCGC ACGAAGCTTCTGTGA CGATTGCTGGGTGTG GTGAACGAGGCCGCA CGAAGCTTCTGTGAT GATTGCTGGGTGTGG TGAACGAGGCCGCAA GAAGCTTCTGTGATG ATTGCTGGGTGTGGT GAACGAGGCCGCAAG AAGCTTCTGTGATGA TTGCTGGGTGTGGTG AACGAGGCCGCAAGC AGCTTCTGTGATGAA TGCTGGGTGTGGTGT ACGAGGCCGCAAGCA GCTTCTGTGATGAAG GCTGGGTGTGGTGTC CTGGGTGTGGTGTCC ACTGATGACACGGGG GGCCAGAAATGGAGA TGGGTGTGGTGTCCC CTGATGACACGGGGC GCCAGAAATGGAGAA GGGTGTGGTGTCCCA TGATGACACGGGGCG CCAGAAATGGAGAAT GGTGTGGTGTCCCAA GATGACACGGGGCGA CAGAAATGGAGAATA GTGTGGTGTCCCAAG ATGACACGGGGCGAT AGAAATGGAGAATAA TGTGGTGTCCCAAGG TGACACGGGGCGATC GAAATGGAGAATAAT GTGGTGTCCCAAGGC GACACGGGGCGATCT AAATGGAGAATAATC TGGTGTCCCAAGGCC ACACGGGGCGATCTC AATGGAGAATAATCC GGTGTCCCAAGGCCA CACGGGGCGATCTCA ATGGAGAATAATCCA GTGTCCCAAGGCCAG ACGGGGCGATCTCAA TGGAGAATAATCCAG TGTCCCAAGGCCAGC CGGGGCGATCTCAAA GGAGAATAATCCAGT GTCCCAAGGCCAGCC GGGGCGATCTCAAAA GAGAATAATCCAGTC TCCCAAGGCCAGCCA GGGCGATCTCAAAAG AGAATAATCCAGTCC CCCAAGGCCAGCCAA GGCGATCTCAAAAGT GAATAATCCAGTCCT CCAAGGCCAGCCAAC GCGATCTCAAAAGTT AATAATCCAGTCCTA CAAGGCCAGCCAACA CGATCTCAAAAGTTA ATAATCCAGTCCTAG AAGGCCAGCCAACAC GATCTCAAAAGTTAT TAATCCAGTCCTAGC AGGCCAGCCAACACT ATCTCAAAAGTTATC AATCCAGTCCTAGCA GGCCAGCCAACACTG TCTCAAAAGTTATCT ATCCAGTCCTAGCAC GCCAGCCAACACTGG CTCAAAAGTTATCTC TCCAGTCCTAGCACC CCAGCCAACACTGGT TCAAAAGTTATCTCC CCAGTCCTAGCACCT CAGCCAACACTGGTC CAAAAGTTATCTCCG CAGTCCTAGCACCTC AGCCAACACTGGTCA AAAAGTTATCTCCGG AGTCCTAGCACCTCC GCCAACACTGGTCAT AAAGTTATCTCCGGT GTCCTAGCACCTCCA CCAACACTGGTCATC AAGTTATCTCCGGTC TCCTAGCACCTCCAA CAACACTGGTCATCA AGTTATCTCCGGTCT CCTAGCACCTCCAAG AACACTGGTCATCAT GTTATCTCCGGTCTC CTAGCACCTCCAAGC ACACTGGTCATCATG TTATCTCCGGTCTCT TAGCACCTCCAAGCC CACTGGTCATCATGG TATCTCCGGTCTCTG AGCACCTCCAAGCCT ACTGGTCATCATGGA ATCTCCGGTCTCTGA GCACCTCCAAGCCTG CTGGTCATCATGGAA TCTCCGGTCTCTGAG CACCTCCAAGCCTGA TGGTCATCATGGAAC CTCCGGTCTCTGAGG ACCTCCAAGCCTGAG GGTCATCATGGAACT TCCGGTCTCTGAGGC CCTCCAAGCCTGAGC GTCATCATGGAACTG CCGGTCTCTGAGGCC CTCCAAGCCTGAGCA TCATCATGGAACTGA CGGTCTCTGAGGCCA TCCAAGCCTGAGCAA CATCATGGAACTGAT GGTCTCTGAGGCCAG CCAAGCCTGAGCAAG ATCATGGAACTGATG GTCTCTGAGGCCAGA CAAGCCTGAGCAAGA TCATGGAACTGATGA TCTCTGAGGCCAGAA AAGCCTGAGCAAGAT CATGGAACTGATGAC CTCTGAGGCCAGAAA AGCCTGAGCAAGATG ATGGAACTGATGACA TCTGAGGCCAGAAAT GCCTGAGCAAGATGA TGGAACTGATGACAC CTGAGGCCAGAAATG CCTGAGCAAGATGAT GGAACTGATGACACG TGAGGCCAGAAATGG CTGAGCAAGATGATT GAACTGATGACACGG GAGGCCAGAAATGGA TGAGCAAGATGATTC AACTGATGACACGGG AGGCCAGAAATGGAG GAGCAAGATGATTCA AGCAAGATGATTCAG ATACCTCAACGCCAA GGAATTGCATGGTAG GCAAGATGATTCAGA TACCTCAACGCCAAT GAATTGCATGGTAGC CAAGATGATTCAGAT ACCTCAACGCCAATA AATTGCATGGTAGCC AAGATGATTCAGATG CCTCAACGCCAATAA ATTGCATGGTAGCCG AGATGATTCAGATGG CTCAACGCCAATAAG TTGCATGGTAGCCGA GATGATTCAGATGGC TCAACGCCAATAAGT TGCATGGTAGCCGAA ATGATTCAGATGGCC CAACGCCAATAAGTT GCATGGTAGCCGAAG TGATTCAGATGGCCG AACGCCAATAAGTTC CATGGTAGCCGAAGA GATTCAGATGGCCGG ACGCCAATAAGTTCG ATGGTAGCCGAAGAT ATTCAGATGGCCGGA CGCCAATAAGTTCGT TGGTAGCCGAAGATT TTCAGATGGCCGGAG GCCAATAAGTTCGTC GGTAGCCGAAGATTT TCAGATGGCCGGAGA CCAATAAGTTCGTCC GTAGCCGAAGATTTC CAGATGGCCGGAGAG CAATAAGTTCGTCCA TAGCCGAAGATTTCA AGATGGCCGGAGAGA AATAAGTTCGTCCAC AGCCGAAGATTTCAC GATGGCCGGAGAGAT ATAAGTTCGTCCACA GCCGAAGATTTCACA ATGGCCGGAGAGATT TAAGTTCGTCCACAG CCGAAGATTTCACAG TGGCCGGAGAGATTG AAGTTCGTCCACAGA CGAAGATTTCACAGT GGCCGGAGAGATTGC AGTTCGTCCACAGAG GAAGATTTCACAGTC GCCGGAGAGATTGCA GTTCGTCCACAGAGA AAGATTTCACAGTCA CCGGAGAGATTGCAG TTCGTCCACAGAGAC AGATTTCACAGTCAA CGGAGAGATTGCAGA TCGTCCACAGAGACC GATTTCACAGTCAAA GGAGAGATTGCAGAC CGTCCACAGAGACCT ATTTCACAGTCAAAA GAGAGATTGCAGACG GTCCACAGAGACCTT TTTCACAGTCAAAAT AGAGATTGCAGACGG TCCACAGAGACCTTG TTCACAGTCAAAATC GAGATTGCAGACGGC CCACAGAGACCTTGC TCACAGTCAAAATCG AGATTGCAGACGGCA CACAGAGACCTTGCT CACAGTCAAAATCGG GATTGCAGACGGCAT ACAGAGACCTTGCTG ACAGTCAAAATCGGA ATTGCAGACGGCATG CAGAGACCTTGCTGC CAGTCAAAATCGGAG TTGCAGACGGCATGG AGAGACCTTGCTGCC AGTCAAAATCGGAGA TGCAGACGGCATGGC GAGACCTTGCTGCCC GTCAAAATCGGAGAT GCAGACGGCATGGCA AGACCTTGCTGCCCG TCAAAATCGGAGATT CAGACGGCATGGCAT GACCTTGCTGCCCGG CAAAATCGGAGATTT AGACGGCATGGCATA ACCTTGCTGCCCGGA AAAATCGGAGATTTT GACGGCATGGCATAC CCTTGCTGCCCGGAA AAATCGGAGATTTTG ACGGCATGGCATACC CTTGCTGCCCGGAAT AATCGGAGATTTTGG CGGCATGGCATACCT TTGCTGCCCGGAATT ATCGGAGATTTTGGT GGCATGGCATACCTC TGCTGCCCGGAATTG TCGGAGATTTTGGTA GCATGGCATACCTCA GCTGCCCGGAATTGC CGGAGATTTTGGTAT CATGGCATACCTCAA CTGCCCGGAATTGCA GGAGATTTTGGTATG ATGGCATACCTCAAC TGCCCGGAATTGCAT GAGATTTTGGTATGA TGGCATACCTCAACG GCCCGGAATTGCATG AGATTTTGGTATGAC GGCATACCTCAACGC CCCGGAATTGCATGG GATTTTGGTATGACG GCATACCTCAACGCC CCGGAATTGCATGGT ATTTTGGTATGACGC CATACCTCAACGCCA CGGAATTGCATGGTA TTTTGGTATGACGCG TTTGGTATGACGCGA AGGAGGCAAAGGGCT CCCTCAAGGATGGAG TTGGTATGACGCGAG GGAGGCAAAGGGCTG CCTCAAGGATGGAGT TGGTATGACGCGAGA GAGGCAAAGGGCTGC CTCAAGGATGGAGTC GGTATGACGCGAGAT AGGCAAAGGGCTGCT TCAAGGATGGAGTCT GTATGACGCGAGATA GGCAAAGGGCTGCTG CAAGGATGGAGTCTT TATGACGCGAGATAT GCAAAGGGCTGCTGC AAGGATGGAGTCTTC ATGACGCGAGATATC CAAAGGGCTGCTGCC AGGATGGAGTCTTCA TGACGCGAGATATCT AAAGGGCTGCTGCCC GGATGGAGTCTTCAC GACGCGAGATATCTA AAGGGCTGCTGCCCG GATGGAGTCTTCACC ACGCGAGATATCTAT AGGGCTGCTGCCCGT ATGGAGTCTTCACCA CGCGAGATATCTATG GGGCTGCTGCCCGTG TGGAGTCTTCACCAC GCGAGATATCTATGA GGCTGCTGCCCGTGC GGAGTCTTCACCACT CGAGATATCTATGAG GCTGCTGCCCGTGCG GAGTCTTCACCACTT GAGATATCTATGAGA CTGCTGCCCGTGCGC AGTCTTCACCACTTA AGATATCTATGAGAC TGCTGCCCGTGCGCT GTCTTCACCACTTAC GATATCTATGAGACA GCTGCCCGTGCGCTG TCTTCACCACTTACT ATATCTATGAGACAG CTGCCCGTGCGCTGG CTTCACCACTTACTC TATCTATGAGACAGA TGCCCGTGCGCTGGA TTCACCACTTACTCG ATCTATGAGACAGAC GCCCGTGCGCTGGAT TCACCACTTACTCGG TCTATGAGACAGACT CCCGTGCGCTGGATG CACCACTTACTCGGA CTATGAGACAGACTA CCGTGCGCTGGATGT ACCACTTACTCGGAC TATGAGACAGACTAT CGTGCGCTGGATGTC CCACTTACTCGGACG ATGAGACAGACTATT GTGCGCTGGATGTCT CACTTACTCGGACGT TGAGACAGACTATTA TGCGCTGGATGTCTC ACTTACTCGGACGTC GAGACAGACTATTAC GCGCTGGATGTCTCC CTTACTCGGACGTCT AGACAGACTATTACC CGCTGGATGTCTCCT TTACTCGGACGTCTG GACAGACTATTACCG GCTGGATGTCTCCTG TACTCGGACGTCTGG ACAGACTATTACCGG CTGGATGTCTCCTGA ACTCGGACGTCTGGT CAGACTATTACCGGA TGGATGTCTCCTGAG CTCGGACGTCTGGTC AGACTATTACCGGAA GGATGTCTCCTGAGT TCGGACGTCTGGTCC GACTATTACCGGAAA GATGTCTCCTGAGTC CGGACGTCTGGTCCT ACTATTACCGGAAAG ATGTCTCCTGAGTCC GGACGTCTGGTCCTT CTATTACCGGAAAGG TGTCTCCTGAGTCCC GACGTCTGGTCCTTC TATTACCGGAAAGGA GTCTCCTGAGTCCCT ACGTCTGGTCCTTCG ATTACCGGAAAGGAG TCTCCTGAGTCCCTC CGTCTGGTCCTTCGG TTACCGGAAAGGAGG CTCCTGAGTCCCTCA GTCTGGTCCTTCGGG TACCGGAAAGGAGGC TCCTGAGTCCCTCAA TCTGGTCCTTCGGGG ACCGGAAAGGAGGCA CCTGAGTCCCTCAAG CTGGTCCTTCGGGGT CCGGAAAGGAGGCAA CTGAGTCCCTCAAGG TGGTCCTTCGGGGTC CGGAAAGGAGGCAAA TGAGTCCCTCAAGGA GGTCCTTCGGGGTCG GGAAAGGAGGCAAAG GAGTCCCTCAAGGAT GTCCTTCGGGGTCGT GAAAGGAGGCAAAGG AGTCCCTCAAGGATG TCCTTCGGGGTCGTC AAAGGAGGCAAAGGG GTCCCTCAAGGATGG CCTTCGGGGTCGTCC AAGGAGGCAAAGGGC TCCCTCAAGGATGGA CTTCGGGGTCGTCCT TTCGGGGTCGTCCTC CTACCAGGGCTTGTC AGGGCGGCCTTCTGG TCGGGGTCGTCCTCT TACCAGGGCTTGTCC GGGCGGCCTTCTGGA CGGGGTCGTCCTCTG ACCAGGGCTTGTCCA GGCGGCCTTCTGGAC GGGGTCGTCCTCTGG CCAGGGCTTGTCCAA GCGGCCTTCTGGACA GGGTCGTCCTCTGGG CAGGGCTTGTCCAAC CGGCCTTCTGGACAA GGTCGTCCTCTGGGA AGGGCTTGTCCAACG GGCCTTCTGGACAAG GTCGTCCTCTGGGAG GGGCTTGTCCAACGA GCCTTCTGGACAAGC TCGTCCTCTGGGAGA GGCTTGTCCAACGAG CCTTCTGGACAAGCC CGTCCTCTGGGAGAT GCTTGTCCAACGAGC CTTCTGGACAAGCCA GTCCTCTGGGAGATC CTTGTCCAACGAGCA TTCTGGACAAGCCAG TCCTCTGGGAGATCG TTGTCCAACGAGCAA TCTGGACAAGCCAGA CCTCTGGGAGATCGC TGTCCAACGAGCAAG CTGGACAAGCCAGAC CTCTGGGAGATCGCC GTCCAACGAGCAAGT TGGACAAGCCAGACA TCTGGGAGATCGCCA TCCAACGAGCAAGTC GGACAAGCCAGACAA CTGGGAGATCGCCAC CCAACGAGCAAGTCC GACAAGCCAGACAAC TGGGAGATCGCCACA CAACGAGCAAGTCCT ACAAGCCAGACAACT GGGAGATCGCCACAC AACGAGCAAGTCCTT CAAGCCAGACAACTG GGAGATCGCCACACT ACGAGCAAGTCCTTC AAGCCAGACAACTGT GAGATCGCCACACTG CGAGCAAGTCCTTCG AGCCAGACAACTGTC AGATCGCCACACTGG GAGCAAGTCCTTCGC GCCAGACAACTGTCC GATCGCCACACTGGC AGCAAGTCCTTCGCT CCAGACAACTGTCCT ATCGCCACACTGGCC GCAAGTCCTTCGCTT CAGACAACTGTCCTG TCGCCACACTGGCCG CAAGTCCTTCGCTTC AGACAACTGTCCTGA CGCCACACTGGCCGA AAGTCCTTCGCTTCG GACAACTGTCCTGAC GCCACACTGGCCGAG AGTCCTTCGCTTCGT ACAACTGTCCTGACA CCACACTGGCCGAGC GTCCTTCGCTTCGTC CAACTGTCCTGACAT CACACTGGCCGAGCA TCCTTCGCTTCGTCA AACTGTCCTGACATG ACACTGGCCGAGCAG CCTTCGCTTCGTCAT ACTGTCCTGACATGC CACTGGCCGAGCAGC CTTCGCTTCGTCATG CTGTCCTGACATGCT ACTGGCCGAGCAGCC TTCGCTTCGTCATGG TGTCCTGACATGCTG CTGGCCGAGCAGCCC TCGCTTCGTCATGGA GTCCTGACATGCTGT TGGCCGAGCAGCCCT CGCTTCGTCATGGAG TCCTGACATGCTGTT GGCCGAGCAGCCCTA GCTTCGTCATGGAGG CCTGACATGCTGTTT GCCGAGCAGCCCTAC CTTCGTCATGGAGGG CTGACATGCTGTTTG CCGAGCAGCCCTACC TTCGTCATGGAGGGC TGACATGCTGTTTGA CGAGCAGCCCTACCA TCGTCATGGAGGGCG GACATGCTGTTTGAA GAGCAGCCCTACCAG CGTCATGGAGGGCGG ACATGCTGTTTGAAC AGCAGCCCTACCAGG GTCATGGAGGGCGGC CATGCTGTTTGAACT GCAGCCCTACCAGGG TCATGGAGGGCGGCC ATGCTGTTTGAACTG CAGCCCTACCAGGGC CATGGAGGGCGGCCT TGCTGTTTGAACTGA AGCCCTACCAGGGCT ATGGAGGGCGGCCTT GCTGTTTGAACTGAT GCCCTACCAGGGCTT TGGAGGGCGGCCTTC CTGTTTGAACTGATG CCCTACCAGGGCTTG GGAGGGCGGCCTTCT TGTTTGAACTGATGC CCTACCAGGGCTTGT GAGGGCGGCCTTCTG GTTTGAACTGATGCG TTTGAACTGATGCGC GCCTTCCTTCCTGGA AGCCTGGCTTCCGGG TTGAACTGATGCGCA CCTTCCTTCCTGGAG GCCTGGCTTCCGGGA TGAACTGATGCGCAT CTTCCTTCCTGGAGA CCTGGCTTCCGGGAG GAACTGATGCGCATG TTCCTTCCTGGAGAT CTGGCTTCCGGGAGG AACTGATGCGCATGT TCCTTCCTGGAGATC TGGCTTCCGGGAGGT ACTGATGCGCATGTG CCTTCCTGGAGATCA GGCTTCCGGGAGGTC CTGATGCGCATGTGC CTTCCTGGAGATCAT GCTTCCGGGAGGTCT TGATGCGCATGTGCT TTCCTGGAGATCATC CTTCCGGGAGGTCTC GATGCGCATGTGCTG TCCTGGAGATCATCA TTCCGGGAGGTCTCC ATGCGCATGTGCTGG CCTGGAGATCATCAG TCCGGGAGGTCTCCT TGCGCATGTGCTGGC CTGGAGATCATCAGC CCGGGAGGTCTCCTT GCGCATGTGCTGGCA TGGAGATCATCAGCA CGGGAGGTCTCCTTC CGCATGTGCTGGCAG GGAGATCATCAGCAG GGGAGGTCTCCTTCT GCATGTGCTGGCAGT GAGATCATCAGCAGC GGAGGTCTCCTTCTA CATGTGCTGGCAGTA AGATCATCAGCAGCA GAGGTCTCCTTCTAC ATGTGCTGGCAGTAT GATCATCAGCAGCAT AGGTCTCCTTCTACT TGTGCTGGCAGTATA ATCATCAGCAGCATC GGTCTCCTTCTACTA GTGCTGGCAGTATAA TCATCAGCAGCATCA GTCTCCTTCTACTAC TGCTGGCAGTATAAC CATCAGCAGCATCAA TCTCCTTCTACTACA GCTGGCAGTATAACC ATCAGCAGCATCAAA CTCCTTCTACTACAG CTGGCAGTATAACCC TCAGCAGCATCAAAG TCCTTCTACTACAGC TGGCAGTATAACCCC CAGCAGCATCAAAGA CCTTCTACTACAGCG GGCAGTATAACCCCA AGCAGCATCAAAGAG CTTCTACTACAGCGA GCAGTATAACCCCAA GCAGCATCAAAGAGG TTCTACTACAGCGAG CAGTATAACCCCAAG CAGCATCAAAGAGGA TCTACTACAGCGAGG AGTATAACCCCAAGA AGCATCAAAGAGGAG CTACTACAGCGAGGA GTATAACCCCAAGAT GCATCAAAGAGGAGA TACTACAGCGAGGAG TATAACCCCAAGATG CATCAAAGAGGAGAT ACTACAGCGAGGAGA ATAACCCCAAGATGA ATCAAAGAGGAGATG CTACAGCGAGGAGAA TAACCCCAAGATGAG TCAAAGAGGAGATGG TACAGCGAGGAGAAC AACCCCAAGATGAGG CAAAGAGGAGATGGA ACAGCGAGGAGAACA ACCCCAAGATGAGGC AAAGAGGAGATGGAG CAGCGAGGAGAACAA CCCCAAGATGAGGCC AAGAGGAGATGGAGC AGCGAGGAGAACAAG CCCAAGATGAGGCCT AGAGGAGATGGAGCC GCGAGGAGAACAAGC CCAAGATGAGGCCTT GAGGAGATGGAGCCT CGAGGAGAACAAGCT CAAGATGAGGCCTTC AGGAGATGGAGCCTG GAGGAGAACAAGCTG AAGATGAGGCCTTCC GGAGATGGAGCCTGG AGGAGAACAAGCTGC AGATGAGGCCTTCCT GAGATGGAGCCTGGC GGAGAACAAGCTGCC GATGAGGCCTTCCTT AGATGGAGCCTGGCT GAGAACAAGCTGCCC ATGAGGCCTTCCTTC GATGGAGCCTGGCTT AGAACAAGCTGCCCG TGAGGCCTTCCTTCC ATGGAGCCTGGCTTC GAACAAGCTGCCCGA GAGGCCTTCCTTCCT TGGAGCCTGGCTTCC AACAAGCTGCCCGAG AGGCCTTCCTTCCTG GGAGCCTGGCTTCCG ACAAGCTGCCCGAGC GGCCTTCCTTCCTGG GAGCCTGGCTTCCGG CAAGCTGCCCGAGCC AAGCTGCCCGAGCCG GGAGAGCGTCCCCCT CACTGCCCGACAGAC AGCTGCCCGAGCCGG GAGAGCGTCCCCCTG ACTGCCCGACAGACA GCTGCCCGAGCCGGA AGAGCGTCCCCCTGG CTGCCCGACAGACAC CTGCCCGAGCCGGAG GAGCGTCCCCCTGGA TGCCCGACAGACACT TGCCCGAGCCGGAGG AGCGTCCCCCTGGAC GCCCGACAGACACTC GCCCGAGCCGGAGGA GCGTCCCCCTGGACC CCCGACAGACACTCA CCCGAGCCGGAGGAG CGTCCCCCTGGACCC CCGACAGACACTCAG CCGAGCCGGAGGAGC GTCCCCCTGGACCCC CGACAGACACTCAGG CGAGCCGGAGGAGCT TCCCCCTGGACCCCT GACAGACACTCAGGA GAGCCGGAGGAGCTG CCCCCTGGACCCCTC ACAGACACTCAGGAC AGCCGGAGGAGCTGG CCCCTGGACCCCTCG CAGACACTCAGGACA GCCGGAGGAGCTGGA CCCTGGACCCCTCGG AGACACTCAGGACAC CCGGAGGAGCTGGAC CCTGGACCCCTCGGC GACACTCAGGACACA CGGAGGAGCTGGACC CTGGACCCCTCGGCC ACACTCAGGACACAA GGAGGAGCTGGACCT TGGACCCCTCGGCCT CACTCAGGACACAAG GAGGAGCTGGACCTG GGACCCCTCGGCCTC ACTCAGGACACAAGG AGGAGCTGGACCTGG GACCCCTCGGCCTCC CTCAGGACACAAGGC GGAGCTGGACCTGGA ACCCCTCGGCCTCCT TCAGGACACAAGGCC GAGCTGGACCTGGAG CCCCTCGGCCTCCTC CAGGACACAAGGCCG AGCTGGACCTGGAGC CCCTCGGCCTCCTCG AGGACACAAGGCCGA GCTGGACCTGGAGCC CCTCGGCCTCCTCGT GGACACAAGGCCGAG CTGGACCTGGAGCCA CTCGGCCTCCTCGTC GACACAAGGCCGAGA TGGACCTGGAGCCAG TCGGCCTCCTCGTCC ACACAAGGCCGAGAA GGACCTGGAGCCAGA CGGCCTCCTCGTCCT CACAAGGCCGAGAAC GACCTGGAGCCAGAG GGCCTCCTCGTCCTC ACAAGGCCGAGAACG ACCTGGAGCCAGAGA GCCTCCTCGTCCTCC CAAGGCCGAGAACGG CCTGGAGCCAGAGAA CCTCCTCGTCCTCCC AAGGCCGAGAACGGC CTGGAGCCAGAGAAC CTCCTCGTCCTCCCT AGGCCGAGAACGGCC TGGAGCCAGAGAACA TCCTCGTCCTCCCTG GGCCGAGAACGGCCC GGAGCCAGAGAACAT CCTCGTCCTCCCTGC GCCGAGAACGGCCCC GAGCCAGAGAACATG CTCGTCCTCCCTGCC CCGAGAACGGCCCCG AGCCAGAGAACATGG TCGTCCTCCCTGCCA CGAGAACGGCCCCGG GCCAGAGAACATGGA CGTCCTCCCTGCCAC GAGAACGGCCCCGGC CCAGAGAACATGGAG GTCCTCCCTGCCACT AGAACGGCCCCGGCC CAGAGAACATGGAGA TCCTCCCTGCCACTG GAACGGCCCCGGCCC AGAGAACATGGAGAG CCTCCCTGCCACTGC AACGGCCCCGGCCCT GAGAACATGGAGAGC CTCCCTGCCACTGCC ACGGCCCCGGCCCTG AGAACATGGAGAGCG TCCCTGCCACTGCCC CGGCCCCGGCCCTGG GAACATGGAGAGCGT CCCTGCCACTGCCCG GGCCCCGGCCCTGGG AACATGGAGAGCGTC CCTGCCACTGCCCGA GCCCCGGCCCTGGGG ACATGGAGAGCGTCC CTGCCACTGCCCGAC CCCCGGCCCTGGGGT CATGGAGAGCGTCCC TGCCACTGCCCGACA CCCGGCCCTGGGGTG ATGGAGAGCGTCCCC GCCACTGCCCGACAG CCGGCCCTGGGGTGC TGGAGAGCGTCCCCC CCACTGCCCGACAGA CGGCCCTGGGGTGCT GGCCCTGGGGTGCTG GCCTTACGCCCACAT TGCCGCTGCCCCAGT GCCCTGGGGTGCTGG CCTTACGCCCACATG GCCGCTGCCCCAGTC CCCTGGGGTGCTGGT CTTACGCCCACATGA CCGCTGCCCCAGTCT CCTGGGGTGCTGGTC TTACGCCCACATGAA CGCTGCCCCAGTCTT CTGGGGTGCTGGTCC TACGCCCACATGAAC GCTGCCCCAGTCTTC TGGGGTGCTGGTCCT ACGCCCACATGAACG CTGCCCCAGTCTTCG GGGGTGCTGGTCCTC CGCCCACATGAACGG TGCCCCAGTCTTCGA GGGTGCTGGTCCTCC GCCCACATGAACGGG GCCCCAGTCTTCGAC GGTGCTGGTCCTCCG CCCACATGAACGGGG CCCCAGTCTTCGACC GTGCTGGTCCTCCGC CCACATGAACGGGGG CCCAGTCTTCGACCT TGCTGGTCCTCCGCG CACATGAACGGGGGC CCAGTCTTCGACCTG GCTGGTCCTCCGCGC ACATGAACGGGGGCC CAGTCTTCGACCTGC CTGGTCCTCCGCGCC CATGAACGGGGGCCG AGTCTTCGACCTGCT TGGTCCTCCGCGCCA ATGAACGGGGGCCGC GTCTTCGACCTGCTG GGTCCTCCGCGCCAG TGAACGGGGGCCGCA TCTTCGACCTGCTGA GTCCTCCGCGCCAGC GAACGGGGGCCGCAA CTTCGACCTGCTGAT TCCTCCGCGCCAGCT AACGGGGGCCGCAAG TTCGACCTGCTGATC CCTCCGCGCCAGCTT ACGGGGGCCGCAAGA TCGACCTGCTGATCC CTCCGCGCCAGCTTC CGGGGGCCGCAAGAA CGACCTGCTGATCCT TCCGCGCCAGCTTCG GGGGGCCGCAAGAAC GACCTGCTGATCCTT CCGCGCCAGCTTCGA GGGGCCGCAAGAACG ACCTGCTGATCCTTG CGCGCCAGCTTCGAC GGGCCGCAAGAACGA CCTGCTGATCCTTGG GCGCCAGCTTCGACG GGCCGCAAGAACGAG CTGCTGATCCTTGGA CGCCAGCTTCGACGA GCCGCAAGAACGAGC TGCTGATCCTTGGAT GCCAGCTTCGACGAG CCGCAAGAACGAGCG GCTGATCCTTGGATC CCAGCTTCGACGAGA CGCAAGAACGAGCGG CTGATCCTTGGATCC CAGCTTCGACGAGAG GCAAGAACGAGCGGG TGATCCTTGGATCCT AGCTTCGACGAGAGA CAAGAACGAGCGGGC GATCCTTGGATCCTG GCTTCGACGAGAGAC AAGAACGAGCGGGCC ATCCTTGGATCCTGA CTTCGACGAGAGACA AGAACGAGCGGGCCT TCCTTGGATCCTGAA TTCGACGAGAGACAG GAACGAGCGGGCCTT CCTTGGATCCTGAAT TCGACGAGAGACAGC AACGAGCGGGCCTTG CTTGGATCCTGAATC CGACGAGAGACAGCC ACGAGCGGGCCTTGC TTGGATCCTGAATCT GACGAGAGACAGCCT CGAGCGGGCCTTGCC TGGATCCTGAATCTG ACGAGAGACAGCCTT GAGCGGGCCTTGCCG GGATCCTGAATCTGT CGAGAGACAGCCTTA AGCGGGCCTTGCCGC GATCCTGAATCTGTG GAGAGACAGCCTTAC GCGGGCCTTGCCGCT ATCCTGAATCTGTGC AGAGACAGCCTTACG CGGGCCTTGCCGCTG TCCTGAATCTGTGCA GAGACAGCCTTACGC GGGCCTTGCCGCTGC CCTGAATCTGTGCAA AGACAGCCTTACGCC GGCCTTGCCGCTGCC CTGAATCTGTGCAAA GACAGCCTTACGCCC GCCTTGCCGCTGCCC TGAATCTGTGCAAAC ACAGCCTTACGCCCA CCTTGCCGCTGCCCC GAATCTGTGCAAACA CAGCCTTACGCCCAC CTTGCCGCTGCCCCA AATCTGTGCAAACAG AGCCTTACGCCCACA TTGCCGCTGCCCCAG ATCTGTGCAAACAGT TCTGTGCAAACAGTA GGGAGAGAGAGTTTT CAGTGGATCTTCAGT CTGTGCAAACAGTAA GGAGAGAGAGTTTTA AGTGGATCTTCAGTT TGTGCAAACAGTAAC GAGAGAGAGTTTTAA GTGGATCTTCAGTTC GTGCAAACAGTAACG AGAGAGAGTTTTAAC TGGATCTTCAGTTCT TGCAAACAGTAACGT GAGAGAGTTTTAACA GGATCTTCAGTTCTG GCAAACAGTAACGTG AGAGAGTTTTAACAA GATCTTCAGTTCTGC CAAACAGTAACGTGT GAGAGTTTTAACAAT ATCTTCAGTTCTGCC AAACAGTAACGTGTG AGAGTTTTAACAATC TCTTCAGTTCTGCCC AACAGTAACGTGTGC GAGTTTTAACAATCC CTTCAGTTCTGCCCT ACAGTAACGTGTGCG AGTTTTAACAATCCA TTCAGTTCTGCCCTT CAGTAACGTGTGCGC GTTTTAACAATCCAT TCAGTTCTGCCCTTG AGTAACGTGTGCGCA TTTTAACAATCCATT CAGTTCTGCCCTTGC GTAACGTGTGCGCAC TTTAACAATCCATTC AGTTCTGCCCTTGCT TAACGTGTGCGCACG TTAACAATCCATTCA GTTCTGCCCTTGCTG AACGTGTGCGCACGC TAACAATCCATTCAC TTCTGCCCTTGCTGC ACGTGTGCGCACGCG AACAATCCATTCACA TCTGCCCTTGCTGCC CGTGTGCGCACGCGC ACAATCCATTCACAA CTGCCCTTGCTGCCC GTGTGCGCACGCGCA CAATCCATTCACAAG TGCCCTTGCTGCCCG TGTGCGCACGCGCAG AATCCATTCACAAGC GCCCTTGCTGCCCGC GTGCGCACGCGCAGC ATCCATTCACAAGCC CCCTTGCTGCCCGCG TGCGCACGCGCAGCG TCCATTCACAAGCCT CCTTGCTGCCCGCGG GCGCACGCGCAGCGG CCATTCACAAGCCTC CTTGCTGCCCGCGGG CGCACGCGCAGCGGG CATTCACAAGCCTCC TTGCTGCCCGCGGGA GCACGCGCAGCGGGG ATTCACAAGCCTCCT TGCTGCCCGCGGGAG CACGCGCAGCGGGGT TTCACAAGCCTCCTG GCTGCCCGCGGGAGA ACGCGCAGCGGGGTG TCACAAGCCTCCTGT CTGCCCGCGGGAGAC CGCGCAGCGGGGTGG CACAAGCCTCCTGTA TGCCCGCGGGAGACA GCGCAGCGGGGTGGG ACAAGCCTCCTGTAC GCCCGCGGGAGACAG CGCAGCGGGGTGGGG CAAGCCTCCTGTACC CCCGCGGGAGACAGC GCAGCGGGGTGGGGG AAGCCTCCTGTACCT CCGCGGGAGACAGCT CAGCGGGGTGGGGGG AGCCTCCTGTACCTC CGCGGGAGACAGCTT AGCGGGGTGGGGGGG GCCTCCTGTACCTCA GCGGGAGACAGCTTC GCGGGGTGGGGGGGG CCTCCTGTACCTCAG CGGGAGACAGCTTCT CGGGGTGGGGGGGGA CTCCTGTACCTCAGT GGGAGACAGCTTCTC GGGGTGGGGGGGGAG TCCTGTACCTCAGTG GGAGACAGCTTCTCT GGGTGGGGGGGGAGA CCTGTACCTCAGTGG GAGACAGCTTCTCTG GGTGGGGGGGGAGAG CTGTACCTCAGTGGA AGACAGCTTCTCTGC GTGGGGGGGGAGAGA TGTACCTCAGTGGAT GACAGCTTCTCTGCA TGGGGGGGGAGAGAG GTACCTCAGTGGATC ACAGCTTCTCTGCAG GGGGGGGGAGAGAGA TACCTCAGTGGATCT CAGCTTCTCTGCAGT GGGGGGGAGAGAGAG ACCTCAGTGGATCTT AGCTTCTCTGCAGTA GGGGGGAGAGAGAGT CCTCAGTGGATCTTC GCTTCTCTGCAGTAA GGGGGAGAGAGAGTT CTCAGTGGATCTTCA CTTCTCTGCAGTAAA GGGGAGAGAGAGTTT TCAGTGGATCTTCAG TTCTCTGCAGTAAAA TCTCTGCAGTAAAAC CAAGCAGCTTTTTAT CCTTTAAGAACCTTA CTCTGCAGTAAAACA AAGCAGCTTTTTATT CTTTAAGAACCTTAA TCTGCAGTAAAACAC AGCAGCTTTTTATTC TTTAAGAACCTTAAT CTGCAGTAAAACACA GCAGCTTTTTATTCC TTAAGAACCTTAATG TGCAGTAAAACACAT CAGCTTTTTATTCCC TAAGAACCTTAATGA GCAGTAAAACACATT AGCTTTTTATTCCCT AAGAACCTTAATGAC CAGTAAAACACATTT GCTTTTTATTCCCTG AGAACCTTAATGACA AGTAAAACACATTTG CTTTTTATTCCCTGC GAACCTTAATGACAA GTAAAACACATTTGG TTTTTATTCCCTGCC AACCTTAATGACAAC TAAAACACATTTGGG TTTTATTCCCTGCCC ACCTTAATGACAACA AAAACACATTTGGGA TTTATTCCCTGCCCA CCTTAATGACAACAC AAACACATTTGGGAT TTATTCCCTGCCCAA CTTAATGACAACACT AACACATTTGGGATG TATTCCCTGCCCAAA TTAATGACAACACTT ACACATTTGGGATGT ATTCCCTGCCCAAAC TAATGACAACACTTA CACATTTGGGATGTT TTCCCTGCCCAAACC AATGACAACACTTAA ACATTTGGGATGTTC TCCCTGCCCAAACCC ATGACAACACTTAAT CATTTGGGATGTTCC CCCTGCCCAAACCCT TGACAACACTTAATA ATTTGGGATGTTCCT CCTGCCCAAACCCTT GACAACACTTAATAG TTTGGGATGTTCCTT CTGCCCAAACCCTTA ACAACACTTAATAGC TTGGGATGTTCCTTT TGCCCAAACCCTTAA CAACACTTAATAGCA TGGGATGTTCCTTTT GCCCAAACCCTTAAC AACACTTAATAGCAA GGGATGTTCCTTTTT CCCAAACCCTTAACT ACACTTAATAGCAAC GGATGTTCCTTTTTT CCAAACCCTTAACTG CACTTAATAGCAACA GATGTTCCTTTTTTC CAAACCCTTAACTGA ACTTAATAGCAACAG ATGTTCCTTTTTTCA AAACCCTTAACTGAC CTTAATAGCAACAGA TGTTCCTTTTTTCAA AACCCTTAACTGACA TTAATAGCAACAGAG GTTCCTTTTTTCAAT ACCCTTAACTGACAT TAATAGCAACAGAGC TTCCTTTTTTCAATA CCCTTAACTGACATG AATAGCAACAGAGCA TCCTTTTTTCAATAT CCTTAACTGACATGG ATAGCAACAGAGCAC CCTTTTTTCAATATG CTTAACTGACATGGG TAGCAACAGAGCACT CTTTTTTCAATATGC TTAACTGACATGGGC AGCAACAGAGCACTT TTTTTTCAATATGCA TAACTGACATGGGCC GCAACAGAGCACTTG TTTTTCAATATGCAA AACTGACATGGGCCT CAACAGAGCACTTGA TTTTCAATATGCAAG ACTGACATGGGCCTT AACAGAGCACTTGAG TTTCAATATGCAAGC CTGACATGGGCCTTT ACAGAGCACTTGAGA TTCAATATGCAAGCA TGACATGGGCCTTTA CAGAGCACTTGAGAA TCAATATGCAAGCAG GACATGGGCCTTTAA AGAGCACTTGAGAAC CAATATGCAAGCAGC ACATGGGCCTTTAAG GAGCACTTGAGAACC AATATGCAAGCAGCT CATGGGCCTTTAAGA AGCACTTGAGAACCA ATATGCAAGCAGCTT ATGGGCCTTTAAGAA GCACTTGAGAACCAG TATGCAAGCAGCTTT TGGGCCTTTAAGAAC CACTTGAGAACCAGT ATGCAAGCAGCTTTT GGGCCTTTAAGAACC ACTTGAGAACCAGTC TGCAAGCAGCTTTTT GGCCTTTAAGAACCT CTTGAGAACCAGTCT GCAAGCAGCTTTTTA GCCTTTAAGAACCTT TTGAGAACCAGTCTC TGAGAACCAGTCTCC CCTTTCTCTCTCCTC CAAGTCCAGCTGGGA GAGAACCAGTCTCCT CTTTCTCTCTCCTCT AAGTCCAGCTGGGAA AGAACCAGTCTCCTC TTTCTCTCTCCTCTC AGTCCAGCTGGGAAG GAACCAGTCTCCTCA TTCTCTCTCCTCTCT GTCCAGCTGGGAAGC AACCAGTCTCCTCAC TCTCTCTCCTCTCTG TCCAGCTGGGAAGCC ACCAGTCTCCTCACT CTCTCTCCTCTCTGC CCAGCTGGGAAGCCC CCAGTCTCCTCACTC TCTCTCCTCTCTGCT CAGCTGGGAAGCCCT CAGTCTCCTCACTCT CTCTCCTCTCTGCTT AGCTGGGAAGCCCTT AGTCTCCTCACTCTG TCTCCTCTCTGCTTC GCTGGGAAGCCCTTT GTCTCCTCACTCTGT CTCCTCTCTGCTTCA CTGGGAAGCCCTTTT TCTCCTCACTCTGTC TCCTCTCTGCTTCAT TGGGAAGCCCTTTTT CTCCTCACTCTGTCC CCTCTCTGCTTCATA GGGAAGCCCTTTTTA TCCTCACTCTGTCCC CTCTCTGCTTCATAA GGAAGCCCTTTTTAT CCTCACTCTGTCCCT TCTCTGCTTCATAAC GAAGCCCTTTTTATC CTCACTCTGTCCCTG CTCTGCTTCATAACG AAGCCCTTTTTATCA TCACTCTGTCCCTGT TCTGCTTCATAACGG AGCCCTTTTTATCAG CACTCTGTCCCTGTC CTGCTTCATAACGGA GCCCTTTTTATCAGT ACTCTGTCCCTGTCC TGCTTCATAACGGAA CCCTTTTTATCAGTT CTCTGTCCCTGTCCT GCTTCATAACGGAAA CCTTTTTATCAGTTT TCTGTCCCTGTCCTT CTTCATAACGGAAAA CTTTTTATCAGTTTG CTGTCCCTGTCCTTC TTCATAACGGAAAAA TTTTTATCAGTTTGA TGTCCCTGTCCTTCC TCATAACGGAAAAAT TTTTATCAGTTTGAG GTCCCTGTCCTTCCC CATAACGGAAAAATA TTTATCAGTTTGAGG TCCCTGTCCTTCCCT ATAACGGAAAAATAA TTATCAGTTTGAGGA CCCTGTCCTTCCCTG TAACGGAAAAATAAT TATCAGTTTGAGGAA CCTGTCCTTCCCTGT AACGGAAAAATAATT ATCAGTTTGAGGAAG CTGTCCTTCCCTGTT ACGGAAAAATAATTG TCAGTTTGAGGAAGT TGTCCTTCCCTGTTC CGGAAAAATAATTGC CAGTTTGAGGAAGTG GTCCTTCCCTGTTCT GGAAAAATAATTGCC AGTTTGAGGAAGTGG TCCTTCCCTGTTCTC GAAAAATAATTGCCA GTTTGAGGAAGTGGC CCTTCCCTGTTCTCC AAAAATAATTGCCAC TTTGAGGAAGTGGCT CTTCCCTGTTCTCCC AAAATAATTGCCACA TTGAGGAAGTGGCTG TTCCCTGTTCTCCCT AAATAATTGCCACAA TGAGGAAGTGGCTGT TCCCTGTTCTCCCTT AATAATTGCCACAAG GAGGAAGTGGCTGTC CCCTGTTCTCCCTTT ATAATTGCCACAAGT AGGAAGTGGCTGTCC CCTGTTCTCCCTTTC TAATTGCCACAAGTC GGAAGTGGCTGTCCC CTGTTCTCCCTTTCT AATTGCCACAAGTCC GAAGTGGCTGTCCCT TGTTCTCCCTTTCTC ATTGCCACAAGTCCA AAGTGGCTGTCCCTG GTTCTCCCTTTCTCT TTGCCACAAGTCCAG AGTGGCTGTCCCTGT TTCTCCCTTTCTCTC TGCCACAAGTCCAGC GTGGCTGTCCCTGTG TCTCCCTTTCTCTCT GCCACAAGTCCAGCT TGGCTGTCCCTGTGG CTCCCTTTCTCTCTC CCACAAGTCCAGCTG GGCTGTCCCTGTGGC TCCCTTTCTCTCTCC CACAAGTCCAGCTGG GCTGTCCCTGTGGCC CCCTTTCTCTCTCCT ACAAGTCCAGCTGGG CTGTCCCTGTGGCCC TGTCCCTGTGGCCCC CCGTGGGTCATTACA CTTTATCTTTCACCT GTCCCTGTGGCCCCA CGTGGGTCATTACAA TTTATCTTTCACCTT TCCCTGTGGCCCCAT GTGGGTCATTACAAA TTATCTTTCACCTTT CCCTGTGGCCCCATC TGGGTCATTACAAAA TATCTTTCACCTTTC CCTGTGGCCCCATCC GGGTCATTACAAAAA ATCTTTCACCTTTCT CTGTGGCCCCATCCA GGTCATTACAAAAAA TCTTTCACCTTTCTA TGTGGCCCCATCCAA GTCATTACAAAAAAA CTTTCACCTTTCTAG GTGGCCCCATCCAAC TCATTACAAAAAAAC TTTCACCTTTCTAGG TGGCCCCATCCAACC CATTACAAAAAAACA TTCACCTTTCTAGGG GGCCCCATCCAACCA ATTACAAAAAAACAC TCACCTTTCTAGGGA GCCCCATCCAACCAC TTACAAAAAAACACG CACCTTTCTAGGGAC CCCCATCCAACCACT TACAAAAAAACACGT ACCTTTCTAGGGACA CCCATCCAACCACTG ACAAAAAAACACGTG CCTTTCTAGGGACAT CCATCCAACCACTGT CAAAAAAACACGTGG CTTTCTAGGGACATG CATCCAACCACTGTA AAAAAAACACGTGGA TTTCTAGGGACATGA ATCCAACCACTGTAC AAAAAACACGTGGAG TTCTAGGGACATGAA TCCAACCACTGTACA AAAAACACGTGGAGA TCTAGGGACATGAAA CCAACCACTGTACAC AAAACACGTGGAGAT CTAGGGACATGAAAT CAACCACTGTACACA AAACACGTGGAGATG TAGGGACATGAAATT AACCACTGTACACAC AACACGTGGAGATGG AGGGACATGAAATTT ACCACTGTACACACC ACACGTGGAGATGGA GGGACATGAAATTTA CCACTGTACACACCC CACGTGGAGATGGAA GGACATGAAATTTAC CACTGTACACACCCG ACGTGGAGATGGAAA GACATGAAATTTACA ACTGTACACACCCGC CGTGGAGATGGAAAT ACATGAAATTTACAA CTGTACACACCCGCC GTGGAGATGGAAATT CATGAAATTTACAAA TGTACACACCCGCCT TGGAGATGGAAATTT ATGAAATTTACAAAG GTACACACCCGCCTG GGAGATGGAAATTTT TGAAATTTACAAAGG TACACACCCGCCTGA GAGATGGAAATTTTT GAAATTTACAAAGGG ACACACCCGCCTGAC AGATGGAAATTTTTA AAATTTACAAAGGGC CACACCCGCCTGACA GATGGAAATTTTTAC AATTTACAAAGGGCC ACACCCGCCTGACAC ATGGAAATTTTTACC ATTTACAAAGGGCCA CACCCGCCTGACACC TGGAAATTTTTACCT TTTACAAAGGGCCAT ACCCGCCTGACACCG GGAAATTTTTACCTT TTACAAAGGGCCATC CCCGCCTGACACCGT GAAATTTTTACCTTT TACAAAGGGCCATCG CCGCCTGACACCGTG AAATTTTTACCTTTA ACAAAGGGCCATCGT CGCCTGACACCGTGG AATTTTTACCTTTAT CAAAGGGCCATCGTT GCCTGACACCGTGGG ATTTTTACCTTTATC AAAGGGCCATCGTTC CCTGACACCGTGGGT TTTTTACCTTTATCT AAGGGCCATCGTTCA CTGACACCGTGGGTC TTTTACCTTTATCTT AGGGCCATCGTTCAT TGACACCGTGGGTCA TTTACCTTTATCTTT GGGCCATCGTTCATC GACACCGTGGGTCAT TTACCTTTATCTTTC GGCCATCGTTCATCC ACACCGTGGGTCATT TACCTTTATCTTTCA GCCATCGTTCATCCA CACCGTGGGTCATTA ACCTTTATCTTTCAC CCATCGTTCATCCAA ACCGTGGGTCATTAC CCTTTATCTTTCACC CATCGTTCATCCAAG ATCGTTCATCCAAGG GCCAAAATCCTGAAC CTCGTGTCCGGAGGC TCGTTCATCCAAGGC CCAAAATCCTGAACT TCGTGTCCGGAGGCA CGTTCATCCAAGGCT CAAAATCCTGAACTT CGTGTCCGGAGGCAT GTTCATCCAAGGCTG AAAATCCTGAACTTT GTGTCCGGAGGCATG TTCATCCAAGGCTGT AAATCCTGAACTTTC TGTCCGGAGGCATGG TCATCCAAGGCTGTT AATCCTGAACTTTCT GTCCGGAGGCATGGG CATCCAAGGCTGTTA ATCCTGAACTTTCTC TCCGGAGGCATGGGT ATCCAAGGCTGTTAC TCCTGAACTTTCTCC CCGGAGGCATGGGTG TCCAAGGCTGTTACC CCTGAACTTTCTCCC CGGAGGCATGGGTGA CCAAGGCTGTTACCA CTGAACTTTCTCCCT GGAGGCATGGGTGAG CAAGGCTGTTACCAT TGAACTTTCTCCCTC GAGGCATGGGTGAGC AAGGCTGTTACCATT GAACTTTCTCCCTCA AGGCATGGGTGAGCA AGGCTGTTACCATTT AACTTTCTCCCTCAT GGCATGGGTGAGCAT GGCTGTTACCATTTT ACTTTCTCCCTCATC GCATGGGTGAGCATG GCTGTTACCATTTTA CTTTCTCCCTCATCG CATGGGTGAGCATGG CTGTTACCATTTTAA TTTCTCCCTCATCGG ATGGGTGAGCATGGC TGTTACCATTTTAAC TTCTCCCTCATCGGC TGGGTGAGCATGGCA GTTACCATTTTAACG TCTCCCTCATCGGCC GGGTGAGCATGGCAG TTACCATTTTAACGC CTCCCTCATCGGCCC GGTGAGCATGGCAGC TACCATTTTAACGCT TCCCTCATCGGCCCG GTGAGCATGGCAGCT ACCATTTTAACGCTG CCCTCATCGGCCCGG TGAGCATGGCAGCTG CCATTTTAACGCTGC CCTCATCGGCCCGGC GAGCATGGCAGCTGG CATTTTAACGCTGCC CTCATCGGCCCGGCG AGCATGGCAGCTGGT ATTTTAACGCTGCCT TCATCGGCCCGGCGC GCATGGCAGCTGGTT TTTTAACGCTGCCTA CATCGGCCCGGCGCT CATGGCAGCTGGTTG TTTAACGCTGCCTAA ATCGGCCCGGCGCTG ATGGCAGCTGGTTGC TTAACGCTGCCTAAT TCGGCCCGGCGCTGA TGGCAGCTGGTTGCT TAACGCTGCCTAATT CGGCCCGGCGCTGAT GGCAGCTGGTTGCTC AACGCTGCCTAATTT GGCCCGGCGCTGATT GCAGCTGGTTGCTCC ACGCTGCCTAATTTT GCCCGGCGCTGATTC CAGCTGGTTGCTCCA CGCTGCCTAATTTTG CCCGGCGCTGATTCC AGCTGGTTGCTCCAT GCTGCCTAATTTTGC CCGGCGCTGATTCCT GCTGGTTGCTCCATT CTGCCTAATTTTGCC CGGCGCTGATTCCTC CTGGTTGCTCCATTT TGCCTAATTTTGCCA GGCGCTGATTCCTCG TGGTTGCTCCATTTG GCCTAATTTTGCCAA GCGCTGATTCCTCGT GGTTGCTCCATTTGA CCTAATTTTGCCAAA CGCTGATTCCTCGTG GTTGCTCCATTTGAG CTAATTTTGCCAAAA GCTGATTCCTCGTGT TTGCTCCATTTGAGA TAATTTTGCCAAAAT CTGATTCCTCGTGTC TGCTCCATTTGAGAG AATTTTGCCAAAATC TGATTCCTCGTGTCC GCTCCATTTGAGAGA ATTTTGCCAAAATCC GATTCCTCGTGTCCG CTCCATTTGAGAGAC TTTTGCCAAAATCCT ATTCCTCGTGTCCGG TCCATTTGAGAGACA TTTGCCAAAATCCTG TTCCTCGTGTCCGGA CCATTTGAGAGACAC TTGCCAAAATCCTGA TCCTCGTGTCCGGAG CATTTGAGAGACACG TGCCAAAATCCTGAA CCTCGTGTCCGGAGG ATTTGAGAGACACGC TTTGAGAGACACGCT CTGCTGTGCTGCTCA CTGACTAGATTATTA TTGAGAGACACGCTG TGCTGTGCTGCTCAA TGACTAGATTATTAT TGAGAGACACGCTGG GCTGTGCTGCTCAAG GACTAGATTATTATT GAGAGACACGCTGGC CTGTGCTGCTCAAGG ACTAGATTATTATTT AGAGACACGCTGGCG TGTGCTGCTCAAGGC CTAGATTATTATTTG GAGACACGCTGGCGA GTGCTGCTCAAGGCC TAGATTATTATTTGG AGACACGCTGGCGAC TGCTGCTCAAGGCCA AGATTATTATTTGGG GACACGCTGGCGACA GCTGCTCAAGGCCAC GATTATTATTTGGGG ACACGCTGGCGACAC CTGCTCAAGGCCACA ATTATTATTTGGGGG CACGCTGGCGACACA TGCTCAAGGCCACAG TTATTATTTGGGGGA ACGCTGGCGACACAC GCTCAAGGCCACAGG TATTATTTGGGGGAA CGCTGGCGACACACT CTCAAGGCCACAGGC ATTATTTGGGGGAAC GCTGGCGACACACTC TCAAGGCCACAGGCA TTATTTGGGGGAACT CTGGCGACACACTCC CAAGGCCACAGGCAC TATTTGGGGGAACTG TGGCGACACACTCCG AAGGCCACAGGCACA ATTTGGGGGAACTGG GGCGACACACTCCGT AGGCCACAGGCACAC TTTGGGGGAACTGGA GCGACACACTCCGTC GGCCACAGGCACACA TTGGGGGAACTGGAC CGACACACTCCGTCC GCCACAGGCACACAG TGGGGGAACTGGACA GACACACTCCGTCCA CCACAGGCACACAGG GGGGGAACTGGACAC ACACACTCCGTCCAT CACAGGCACACAGGT GGGGAACTGGACACA CACACTCCGTCCATC ACAGGCACACAGGTC GGGAACTGGACACAA ACACTCCGTCCATCC CAGGCACACAGGTCT GGAACTGGACACAAT CACTCCGTCCATCCG AGGCACACAGGTCTC GAACTGGACACAATA ACTCCGTCCATCCGA GGCACACAGGTCTCA AACTGGACACAATAG CTCCGTCCATCCGAC GCACACAGGTCTCAT ACTGGACACAATAGG TCCGTCCATCCGACT CACACAGGTCTCATT CTGGACACAATAGGT CCGTCCATCCGACTG ACACAGGTCTCATTG TGGACACAATAGGTC CGTCCATCCGACTGC CACAGGTCTCATTGC GGACACAATAGGTCT GTCCATCCGACTGCC ACAGGTCTCATTGCT GACACAATAGGTCTT TCCATCCGACTGCCC CAGGTCTCATTGCTT ACACAATAGGTCTTT CCATCCGACTGCCCC AGGTCTCATTGCTTC CACAATAGGTCTTTC CATCCGACTGCCCCT GGTCTCATTGCTTCT ACAATAGGTCTTTCT ATCCGACTGCCCCTG GTCTCATTGCTTCTG CAATAGGTCTTTCTC TCCGACTGCCCCTGC TCTCATTGCTTCTGA AATAGGTCTTTCTCT CCGACTGCCCCTGCT CTCATTGCTTCTGAC ATAGGTCTTTCTCTC CGACTGCCCCTGCTG TCATTGCTTCTGACT TAGGTCTTTCTCTCA GACTGCCCCTGCTGT CATTGCTTCTGACTA AGGTCTTTCTCTCAG ACTGCCCCTGCTGTG ATTGCTTCTGACTAG GGTCTTTCTCTCAGT CTGCCCCTGCTGTGC TTGCTTCTGACTAGA GTCTTTCTCTCAGTG TGCCCCTGCTGTGCT TGCTTCTGACTAGAT TCTTTCTCTCAGTGA GCCCCTGCTGTGCTG GCTTCTGACTAGATT CTTTCTCTCAGTGAA CCCCTGCTGTGCTGC CTTCTGACTAGATTA TTTCTCTCAGTGAAG CCCTGCTGTGCTGCT TTCTGACTAGATTAT TTCTCTCAGTGAAGG CCTGCTGTGCTGCTC TCTGACTAGATTATT TCTCTCAGTGAAGGT CTCTCAGTGAAGGTG TCTCAGTGAAGGTGG CTCAGTGAAGGTGGG TCAGTGAAGGTGGGG CAGTGAAGGTGGGGA AGTGAAGGTGGGGAG GTGAAGGTGGGGAGA TGAAGGTGGGGAGAA GAAGGTGGGGAGAAG AAGGTGGGGAGAAGC AGGTGGGGAGAAGCT GGTGGGGAGAAGCTG GTGGGGAGAAGCTGA TGGGGAGAAGCTGAA GGGGAGAAGCTGAAC GGGAGAAGCTGAACC GGAGAAGCTGAACCG GAGAAGCTGAACCGG AGAAGCTGAACCGGC

EXAMPLE 9

Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR.AS (antisense: 5′-ATCTCTCCGCTTCCTTTC-3′; (<400>10); ref 13) and IGFR.S (sense control: 5′-GAAAGGAAGCGGAGAGAT-3′; (<400>11); ref 13) IGF-I binding to the cell monolayers was then measured as ¹²⁵I-IGF-I.

EXAMPLE 10

The results of this experiment are shown in FIGS. 7 and 8.

HaCaT cells were initially plated in DMEM with 10% v/v serum, then AS oligo experiments were performed in complete “Keratinocyte-SFM” (Gibco) to exclude the influence of exogenous IGFBPs. Oligos were synthesised as phosphorothioate (nuclease-resistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, 5′-GCGCCCGCTGCATGACGCCTGCAAC-3′ (IGFBP-3 start codon); controls: AS2NS, 5′-CGGAGATGCCGCATGCCAGCGCAGG-3′; AS4,

5′-AGGCGGCTGACGGCACTA-3′; AS4NS, 5′-GACAGCGTCGGAGCGATC-3′; IGFRAS, 5′-ATCTCTCCGCTTCCTTTC-3′;

IGFRS, 5′-GAAAGGAAGCGGAGAGAT-3′. Oligos to IGFBP-3 were based on the published sequence of Spratt et al [12]. AS oligos were added to HaCaT monolayers in 0.5 ml medium in 24-well plates at the concentrations and addition frequencies indicated. IGFBP-3 measured in cell-conditioned medium using a dot-blot assay, adapted from the Western ligand blot method of Hossenlopp et al [11], in which 100 μl of conditioned medium was applied to nitrocellulose filters with a vacuum dot-blot apparatus. After drying the membranes at 37° C., relative amounts of IGFBP are determined by ¹²⁵I-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in FIG. 7, where duplicate wells were measured as shown) were analysed and corrected for changes in cell number per well. Relative cell number per well was determined using an amido black dye method, developed specifically for cultured monolayers of HaCaT cells [14]. Cell numbers differed by less than 10% after treatment. For oligos to the IGF receptor, receptor quantitation in intact HaCaT monolayers was by overnight incubation with ¹²⁵I-IGF-I (30,000 cpm/well) at 4° C.

EXAMPLE 11

Experiments involving ribozymes are generally conducted as described in Internaitonal Patent Application No. WO 89/05852 and in Haselhoff and Gerlach [8]. Ribozymes are constructed with a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA which, in this case, encodes IGFBP-2. Activity of ribozymes is measurable on, for example, Northern blots or using animal models such as in the nude mouse model (15; 16) or the “flaky skin” mouse model (17; 18).

EXAMPLE 12

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 13

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 14

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 15

Twenty-one antisense oligonucleotides targeted to mRNA sequences enducing the IGF-1 receptor, and four random oligonucleotides were synthesized. The antisense oligonucleotides are C5-propynyl-dU, dC 15 mer phosphorothioate oligodeoxyribonucleotides. In these oligonucleotides, a phosphorothioate backbone replaces the phosphodiester backbone of naturally occurring DNA. The positions of the 21 sequence specific antisense oligonucleotides relative to the IGF-1 receptor mRNA structure are shown in FIG. 9.

EXAMPLE 16

Experiments were performed to determine the uptake of the antisense oligonucleotides of Example 15 into keratinocytes. Cells of the differentiated human keratinocyte cell line, HaCaT, were incubated for 24 hours in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% (w/v) fetal calf serum (FCS) containing fluorescently labelled oligonucleotide (R451, a randomized sequence oligonucleotide, 30 nM) and cytofectin GSV (2 μg/ml, Glen Research, 44901 Falcon Place, Sterling, Va. 20166, Cat. No. 70-3815-78). Cells were then transferred to oligonucleotide-free medium and fluorescence microcopy and phase contrast images of the cells were obtained. FIG. 10 shows fluorescence microscopy (Panel A) and phase contrast (Panel B) images of uptake of fluorescently labelled oligonucleotide in the majority of cells in a HaCaT monolayer. The degree of uptake obtained with the cationic lipid cytofectin was far greater than the uptake obtained with the next best lipid tried, Tfx-50.

A further experiment was performed to assess the uptake and toxicity associated with the use of cytofectin GSV over five days. Confluent HaCaT keratinocytes were incubated in DMEM containing fluorescently labelled oligonucleotide R451 (30 nM or 100 nM) plus cytofectin GSV (2 μg/ml or 5 μg/ml) over 120 hours, viewed by fluorescence microscopy, tryptan blue stained, and counted. The graphs in FIG. 11 depict uptake (Panel A) and toxicity (Panel B). The proportion of cells containing oligonucleotide remained high over the 120 hour period. The combination of 30 nM oligonucleotide and 2 μg/ml GSV provided optimal uptake and minimal toxicity.

EXAMPLE 17

The twenty-one oligonucleotides of Example 15 were then screened for their ability to inhibit IGF-I receptor mRNA levels in HaCaT cells, in accordance with the teachings herein. HaCaT cells were grown to 90% confluence in DMEM supplemented with 10% (v/v) FCS. Antisense oligonucleotides (30 nM) were completed with cytofectin GSV (2 μg/ml) and added to the cells in the presence of serum. HaCaT keratinocytes were treated with the oligonucleotide/GSV complexes or randomized sequence oligonucleotides (R451, R766), liposome alone (GSV), or were left untreated (UT). Duplicate treatments were performed. Repeat additions of the oligonucleotides/GSV complex were performed at 24, 48 and 76 hours following the first addition. Total RNA was isolated as per the RNAzolB protocol (Biotecx Laboratories, Inc. 6023 South Loop East, Houston, Tex. 77033) 96 hours following the first addition.

IGF-I receptor mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels were simultaneously determined by a ribonuclease (RNase) protection assay. The RNase Protection Assay kit, in vitro transcription kit, and IGF-I receptor and GAPDH DNA templates were obtained from Ambion, Inc. (2130 Woodward St., Houston, Tex. 78744). The amount of IGF-I receptor mRNA in any given sample was expressed as the amount of IGF-I receptor mRNA relative to the amount of GAPDH mRNA. Each oligonucleotide was tested in at least two separate experiments.

FIG. 12 depicts representative results of the screening process. Panel A shows an electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase protection. Molecular weight markers are shown on the right hand side. The full-length probe is shown on the left hand side; G-probe indicates the IGF-I receptor probe. GAPDH protected fragments (G) are seen at 316 bases and IGF-I protected fragments (I) are seen at 276 bases. Exhibit E, Panel B provides a graph indicating the relative level of IGF-I receptor mRNA following each treatment.

The results obtaining from the above screening assays are summarized in FIG. 13. The graph depicts the relative level of IGF-I receptor mRNA after treatment with oligonucleotides complementary to the human IGF-I receptor mRNA (26-86), four randomized sequence oligonucleotides (R1, R4, R7, R9), liposome alone (GSV), or no treatment (UT). Asterisks indicate a significant different in relative IGF-I receptor mRNA as compared to GSV treated cells (n=4-10, p<0.05).

As demonstrated in FIG. 13, treatment with eighteen of the twenty-one oligonucleotides resulted in a significant different in levels of IGF-I receptor mRNA relative to GSV treated cells. Three of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to less than 35% of GSV-treated cells. These antisense oligonucleotides have the following sequences, presented in the 5′ to 3′ direction: #27 UCCGGAGCCAGACUU #64 CACAGUUGCUGCAAG #78 UCUCCGCUUCCUUUC

As further demonstrated in FIG. 13, six of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to between 35 and 50% of GSV-treated cells. These antisense oligonucleotides have the following sequences, presented in the 5′ to 3′ direction: #28 AGCCCCCACAGCGAG #32 GCCUUGGAGAUGAGC #40 UAACAGAGGUCAGCA #42 GGAUCAGGGACCAGU #46 CGGCAAGCUACACAG #50 GGCAGGCAGGCACAC

EXAMPLE 19

Another experiment was performed demonstrating that antisense oligonucleotides targeted to genetic sequences encoding the IGF0I receptor and that reduce IGF-I receptor mRNA levels also inhibit the IGF-I receptor level on the surface of the treated cultured keratinocytes. HaCaT cells were grown to confluence in 24-well plates in DMEM containing 10% (v/v) FCS. Oligodeoxynucleotide and cytofectin GSV were mixed together in serum-free DMEM, and incubated at room temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells. Cells were incubated for 72 hours with 30 nM random sequence or antisense oligonucleotide and 2 μm/ml GSV, or with GSV alone in DMEM containing 10% (v/v) FCS with solutions replaced every 24 hours. This was followed by incubation with oligonucleotide/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37° C. Cells were washed twice with 1 ml cold PBS. Serum-free DMEM containing 10⁻¹⁰M ¹²⁵I-IGF-I was added with or without the IGF-I analogue, des (1-3) IGF-I, at 10⁻¹¹M to 10⁻⁷M. Cells were incubated at 4° C. for 17 hours with gentle shaking, then washed three times with 1 ml cold PBS and lysed in 250 μl 0.5M NaOH/0.1% (v/v) Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a gamma counter. As shown in FIG. 14, treatment of HaCaT keratinocytes with oligonucleotide reduced cell surface IGF-I receptor levels to 30% of levels in untreated keratinocytes or in keratinocytes treated with liposome alone or a random oligonucleotide, R766. As shown in FIG. 15, treatment with oligonucleotide #27 also significantly reduced cell surface IGF-I receptor levels relative to untreated keratinocytes or treatment with liposome alone or random nucleotide R451. As demonstrated in Example 17, oligonucleotides #64 and #27 reduce IGF-I receptor mRNA levels in cultured keratinocytes to less than 35% of GSV-treated cells. Accordingly, the ability of an oligonucleotide to reduce IGF-I receptor mRNA levels in correlated with its ability to reduce cell surface IGF-I receptor levels.

The forgoing Examples demonstrate that antisense oligonucleotides targeted to the IGF-I receptor can be delivered to human keratinocytes in vitro, can inhibit IGF-I receptor mRNA levels in human keratinocytes in vitro, and that inhibition of mRNA levels is correlated with reduction of cell surface IGF-I receptor levels.

EXAMPLE 19

Further experiments demonstrated the efficacy of antisense oligonucleotides targeted to the IGF-I receptor in an in vivo model of psoriasis. An animal model of psoriasis is the human psoriatic skin xenograft model. The skin used in this model contains the true disease state. In this model, reduction in epidermal thickness of psoriatic grafts in response to treatment is positively correlated with efficacy of treatment. Both normal and psoriatic human skin were grated into a thymic (nude) mice in accordance with a thymic (nude) mice in accordance with the methods of Baker et al (1992) Brit. J. Dermatol. 126:105 and Nanney et al (1992) J. Invest. Dermatol, 92:296. Successful grafting was achieved, as demonstrated in FIG. 16, which shows hemotoxylin and eosin (H&E) stained sections of a 49-day old psoriatic human skin graft (Panel B) compared to the histology of the skin graft prior to grafting (Panel A). The histological features of psoriasis present in the pregraft section (e.g., parakeratosis, acanthosis and pronounced rete ridges) are present in the grafts more than seven weeks post grafting.

Using the model, oligonucleotide uptake was measured in epidermal keratinocytes in vivo after intradermal injection. Fluorescently labelled oligonucleotide (R451, 50 μl, 10 μM injection) was intradermally injected into psoriatic and normal skin grafts on a thymic mice. Live confocal microscopy and fluorescence microscopy of fixed sections was then employed.

Using both techniques, oligonucleotide was found to localize in the nucleus of over 90% of basal keratinocytes. FIG. 17 shows the nuclear localization of oligonucleotide in psoriatic skin cells using conventional fluorescence microscopy of a graft that was removed and sectioned after 24 hours.

After establishing oligonucleotide uptake in the in vivo model, a small number of pilots experiments were performed to determine a schedule for treatment of grated mice with antisense oligonucleotides targeted to genetic sequences encoding the IGF-I receptor. The treatment schedule was finalized as follows: Volume Graft of ODN Duration of Number Treatment Injection Concentration Treatment 1-3 Vehicle (PBS) 50 μl — 20 days 4-6 RandomODN#R451 50 μl 10 μM 20 days 7-9 ODN#27 50 μl 10 μM 20 days 10-12 ODN#74 50 μl 10 μM 20 days 13-15 ODN#50 50 μl 10 μM 20 days

As determined above, oligonucleotide #27 (ODN #27) reduced IGF-I receptor mRNA in vitro to less than 35% of GSV-treated cells. Oligonucleotide #50 (ODN#50) reduced IGF-I receptor mRNA in vitro to between 35 and 50% of GSV-treated cells. Oligonucleotide #74 (ODN #74) was not inhibitory to IGF-I receptor mRNA in vitro. In the in vivo model, each mouse received two grafts. Random oligonucleotide or vehicle was injected intradermally in one graft and acted as a control. The second graft was injected with the targeted oligonucleotide. Each graft received an injection every second day for the duration of the treatment.

Histology of representative grafts from each treatment type are shown in FIGS. 18(a)-(d) and 19(a)-(d). Each sheet shows three images of H&E stained sections: the pregraft histology, the control treated graft, and the targeted oligonucleotide treated graft. FIGS. 18(a)-(d) are shown at 100× magnification; FIGS. 19(a)-(d) are shown at 400× magnification. The total cross sectional area of epidermis of each graft was assessed using MCID analysis software. The pooled results from all of the treated grafts are shown in FIG. 20.

As shown in FIGS. 18(a)-(d) and 19(a)-(d), the vehicle-treated (control) grafts were marginally thinner than the pregraft sections. The degree of regression in these experiments (ie., less than 10%) is not significant. A similar amount of marginal thinning of epidermis compared to pregraft also occurred in pilot experiments in which psoriatic grafts were not injected, and thsu it is unlikely that the vehicle itself has any effect. Histological features of psoriasis present in skin samples prior to grafting (clubbing of rete ridges, parakeratosis, acanthosis) were present in these grafts.

The random oliognucleotide treated grafts varied in epidermal thickness after 20 days of treatment. Grafts were either a similar thickness to the pregraft histology, or marginally thinner. Random oligonucleotide treated grafts were in each case significantly thicker than their targeted oligonucleotide treated pairs.

As shown in FIG. 20, the targeted oligonucleotide treated grafts were significantly thinner than the pregraft sections and showed less parakeratosis and clubbing of rete ridges. Antisense oligonucleotides which were effective at reducing IGF-I receptor mRNA levels in vitro (#27 and #50) produced greatere epidermal thinning than an oligonucleotide which was not inhibitory to IGF-I receptor mRNA in vitro (#74). Accordingly, there is a direct correlation between the ability of an oligonucleotide targeted to the IGF-I receptor to inhibit IGF-I receptor mRNA levels in vitro and the efficacy of the oligonucleotide as an anti-psoriasis agent in an in vivo model.

EXAMPLE 20

Another experiment demonstrated that treatment of psoriatic grafts with an oligonucleotide targeted to a genetic sequence encoding the IGF-I receptor results in inhibition of proliferation. Pregrafts from psoriatic patients, control grafts treated with R4541, and grafts treated with oligonucleotide #27 were obtained as described in Example 19. An antibody to the cell cycle-specific nuclear antigen Ki67 was used to immunohistochemically detect actively dividing cells and tereby assess proliferation. The αKi67 antibody (DAKO, Glostrup, Denmark) recognizes the Ki67 antigen transiently expressed in nuclei of proliferating cells during late G₁, S, M and G₂ phases of the cycle and thsu provides a marker for proliferation. Pregraft and graft sections were immunohistochemically processed by standard methods using αKi67 (according to the manufacturer's instructions), peroxidase-conjugated anti-rabbit second stage antibody, and a chromogenic peroxidase substrate.

The results of this experiment are presented in FIG. 21 as immunohistochemical sections at 100× magnification. The top panel of FIG. 21 depicts a pregraft section obtained from a psoriatic patient. The epidermis is thicker than normal and nucleic are evident in the stratum corneum. Ki67 positive cells, appearing as brown dots, are evidence in the basal and suprabasal layers, and indicate actively proliferating cells. The control (R450-treated) graft in the bottom panel of FIG. 21 also exhibits evidence of proliferation, including parakeratosis and Ki67-positive cells appearing as brown-staining nuclei. The center panel of FIG. 21 exhibits the oligonucleotide #27-treated graft. This graft exhibits significantly reduced proliferation as evidenced by normal (thin) epidermis, lack of invaginations, and substantial loss of Ki67-positive cells.

These results indicate that treatment of human psoriatic grafts with an oligonucleotide targeted to mRNA encoding the IGF-I receptor results in inhibition of epidermal proliferation.

EXAMPLE 21

Topical formulations of complexes of oligonucleotides with cytofectin GSV in aqueous or methylcellulose gel formulations were prepared and assessed for uptake of the oligonucleotide by keratinocytes in vivo. The topical formulations contained oligonucleotides complexed with cytofectin GSV in an aqueous solution or methylcellulose carrier, as taught herein. With both aqueous and methylcellulose gel formulations, locatlization of oligonucleotide R451 to nuclei and cytoplasm of keratinocytes in normal human skin grafts on nuce mice was observed. FIG. 22 shows an image from confocal microscopy demonstrating oligonucleotide locatlization in the nuclei and cytoplasm of keratinocytes in normal human skin grafts after topical application of fluroescently labeled oligonucleotide (10 μM R451) complexed with cytofectin GSV (10 μg/ml). FIG. 23 shows an image from confocal microscopy demonstrating that topical application of the same oligonucleotide/GSV concentrations in a 3% (w/v) methylcellulose gel produced similar uptake in the target keratinocyte population. Using an aqueous formulation of oligonucleotide/GSV complexes, penetration of oligonucleotide into the viable epidermis was observed, whereas application of formulations of oliognucleotide complexed with other cationic lipids resulted in localization of oligonucleotide in the stratum corneum.

EXAMPLE 22

Thirteen antisense oligonucleotides targeted to IGFBP-3 were synthesized. The antisense oligonucleotides are C5-propynyl-dU, Dc15 mer phosphorothioate oligodeoxyribonucleotides. FIG. 24 attached hereto is a schematic diagram indicating the position of the thirteen oligonucleotides relative to the IGFBP-3 mRNA structure.

These oligonucleotides were screened for their ability to inhibit IGFBP-3 mRNA levels of HaCaT cells in accordance with the teachings herein. HaCaT cells were grown to 90% confluence in DMEM supplemented with 10% (v/v) FCS, then placed in complete keratinocyte serum free medium (KSFM, Gibco), which has a defined amount of EGF, for 24 hours. Oligonucleotides (30 nM or 100 nM) were complexed with GSV cytofectin (2 μg/ml) and added to cells in complete KSFM to allow oligonucleotides to enter the nucleus before removal of EGF. Repeat additions were performed at three hours (in serum free DMEM, which releases the EGF inhibition of IGFBP-3 mRNA) and again after another 24 hours. HaCaT cells were also treated with randomized sequence oligonucleotides (R121, R451, R766 and R961), liposome alone (GSV) or were left untreated (UT). Total RNA was isolated as described in Example 17, 24 hours after the last treatment. Total RNA (15 μg) was analyzed by Northern analysis and phosphoroimager quantitation for IGFBP-3 and GADPH mRNA. IGFBP-3 mRNA is expressed as the amount of IGFBP-3 mRNA relative to the amount of GAPDH mRNA.

FIGS. 25(a)-(d) provide graphs which depict results in this screening process. In these graphs, R1 and R12 refer to R121; R4, R4(0) and R45 rfer to R451; R7, R7(0) and R76 refer to R766; and R9 and R96 refer to R961. The values were standardized to GSV-treated cells, and data was pooled and statistically analyzed by ANOVA followed by Domet's test to compare each treatment to GSV-treated cells. The pooled data are presented as a bar graph in FIG. 26. As demonstrated, at a concentration of 30 nM, treatment of HaCaT cells with 8 of the 12 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells. At a concentration of 100 nM, treatment with 9 fo the 13 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells.

These experiments demonstrate that antisense oligonucleotides targeted to genetic sequences encoding IGFBP-3 can inhibit IGFBP-3 mRNA levels in human keratinocytes in vitro.

EXAMPLE 23

IGF-I receptor is a potent mitotic signalling molecule for keratinocytes and the human receptor elicits separate intracellular signals that prevent apoptosis (19). It is proposed in accordance with the present invention that inactivation of IGF-I receptors in epidermal keratinocytes will achieve three important outcomes in subsequent UV treatment of lesions:

-   -   (i) Acute epidermal hyperplasia following UV has been suggested         to increase the risk of keratinocyte carcinogenic transformation         (22). By reducing IGF-I receptor expression in the epidermis,         the incidence of epidermal hyperplasia following UV exposure is         likely to be reduced leading to an overall acceleration in         normalization of the lesion and reduced carcinogenic risk.     -   ii) Inhibition of anti-apoptotic action of IGF-I receptor will         enhance the reversal of epidermal thickening and accelerate         normalization of differentiation. Topical or injected IGF-I         receptor antisense as adjunctive treatment will increase         apoptosis in the epidermal layer thereby enhancing the reduction         in acanthosis observed in UV treatments.     -   iii) Survival of keratinocytes, ie. those which evade apoptosis         is likely to occur when cells have damaged DNA. Such mutations         may be in the tumor suppressor region. Consequently, the use of         antisense therapy will result in less frequent selection of         mutated keratinocytes and therefore reduced incidence of basal         cell carcinomas and squamous.

Accordingly, antisense therapy, especially against IGF-I-receptor is useful in combination with UV therapy in the treatment of epidermal hyperplasia.

EXAMPLE 24

HaCaT cells were treated with antisense oligonucleotides directed to IGF-I receptor mRNA. Levels of IGF-I receptor mRNA were then monitored. In essence, confluent HaCaT cells were treated every 24 hours for four days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). FIG. 27(a) is a photographic representation showing representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. FIG. 27(b) is a densitometric quantification of IGF-I receptor mRNA in a HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black) random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar).

EXAMPLE 25

In this example, reduction in total cellular IGF-I receptor protein was monitored following antisense oligonucleotide treatment. Confluence HaCaT cells were treated with 24 hours for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONS (#27, #50 and #64) or the random sequence oligonucleotide, R451. Total cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with antibody specific for the human IGF-I receptor. FIG. 28(a) shows duplicate treated cellular extracts following the IGF-I receptor at the predicted size of 110 kD. FIG. 28(b) is a densitometric quantification of IGF-I receptor protein.

EXAMPLE 26

The reduction in IGF-I receptor numbers was determined on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were tranfected with IGF-I receptor specific AONs #27, #50, #64, a random sequence oligonucleotides (R451) or following treatment with GSV a lipid alone every 24 hours for 4 days. Competition binding assays using ¹²⁵I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I were performed. Results are shown in FIG. 29.

EXAMPLE 27

In this example, the apoptotic protecting effects of IGF-I receptor on keratinocyte cells was tested by following the reduction in keratino cell numbers following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6414 or treated with GSV a lipid alone every 24 hours for 2 days. The cell number was measured in culture wells using a dye binding assay. The results are presented in FIG. 30. The results clearly confirm that the IGF-I receptor exhibits an anti-apoptotic effect. By reducing IGF-I receptor levels using antisense oligonucleotide treatment, the anti-apoptotic effect is interrupted and apoptosis results in the reduction in keratinocyte cell number. Results are shown in FIG. 30.

EXAMPLE 28

This example shows a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides. Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed histologically. The results are shown in FIG. 31. In FIG. 31(a), donor A graft treated with AON #50 showing epidermal thinning compared with the pregraft and control (PBS) treated graft and donor graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. In FIG. 31(b), the mean epidermal cross-sectional area over the full width of grafts is shown as determined by digital image analysis. The results show that epidermal hyperplasia is reversed following the intradermal injection of antisense oligonucleotides.

EXAMPLE 29

FIG. 32 shows the reversal of epidermal hyperplasia correlating with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides. FIG. 32(a) shows a psoriasis lesion prior to grafting and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). FIG. 32(b) shows the same lesion prior to grafting and after oligonucleotide treatment as in FIG. 32(a) but subjected to in situ hybridisation with ³⁵S-labelled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains which are almost eliminated in the epidermis of the lesion treated with IGF-I receptor specific oligonucleotide # 27 (AON #27). This experiment shows that reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides.

EXAMPLE 30

FIG. 33 treatment with oligonucleotides. HaCaT cell monolayers were grown to 90% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for two days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially available ribonuclease protection assay kit. The results show a reduction in IGF-I receptor mRNA in the HaCaT keratinocyte cells.

EXAMPLE 31

FIG. 34 treatment with oligonucleotides. HaCaT cell monolayers were grown to 90% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Cells were lysed in a buffer containing 50 mM HEPES, 150 mM NaCl, 10% v/v glycerol, 1 v/v Trison X-100 and 100 μg/ml aprotinin on ice for 30 minutes, then 30 μg of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane. Membranes were then incubated with anti-IGF-I receptor antibodies C20 (available from Santa Cruz Biotechnology Inc., Santa Cruz, Calif.) for 1 hour at room temperature and developed using the Vistra ECF western blotting kit (Amersham). The results shown in FIG. 34 confirm that IGF-I receptor protein is reduced in HaCaT keratinocytes following treatment with oligonucleotides.

EXAMPLE 32

This example shows a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. The results are shown in FIG. 35. HaCaT cell monolayers were grown at 40% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 3 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell numbers were then measured every 24 hours using the amido black dye binding assay [32]. Results show that HaCaT keratino cells decrease in number following treatment with oligonucleotides due to a reduction in the anti-apoptotic effect of the IGF-I receptor.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

REFERENCES

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1-44. (canceled)
 45. A method for ameliorating a proliferative or inflammatory skin disorder in a mammal, the method comprising contacting a cell in proliferating or inflamed skin with an effective amount of a nucleic acid molecule, or a chemical modification thereof, wherein the modification produces a modified nucleic acid molecule that has the same length and nucleotide sequence as the nucleic acid molecule prior to modification, and wherein the nucleic acid molecule or modified nucleic acid molecule inhibits growth-factor-mediated cell proliferation or inflammation.
 46. The method of claim 45 wherein the proliferative or inflammatory skin disorder is mediated by a growth factor, wherein the growth factor is selected from the group consisting of insulin-like growth factor I (IGF), keratinocyte growth factor (KGF), transforming growth factor (TGF), tumor necrosis factor (TNF), interleukin (IL), basic fibroblast growth factor (bFGF), and a combination thereof.
 47. The method of claim 45, wherein the proliferative or inflammatory skin disorder is selected from the group consisting of psoriasis, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths, and a cancer of the skin.
 48. The method of claim 45, wherein the nucleic acid molecule or modified nucleic acid molecule reduces the level of an IGF, IGF receptor, or IGF-binding protein in the mammal.
 49. The method of claim 45, wherein the nucleic acid molecule or modified nucleic acid molecule is an antisense molecule that reduces the expression of a gene encoding IGF, IGF receptor, or IGF-binding protein.
 50. A method for ameliorating a disease in a mammal, the method comprising contacting a cell in the diseased tissue with an effective amount of a nucleic acid molecule, or a chemical modification thereof, wherein the modification produces a modified nucleic acid molecule that has the same length and nucleotide sequence as the nucleic acid molecule prior to modification, and wherein the nucleic acid molecule or modified nucleic acid molecule is capable of inhibiting growth-factor-mediated cell proliferation or inflammation.
 51. The method of claim 50, wherein the disease is selected from the group consisting of a hyperneovascular condition, neovascular condition of the retina, neovascular condition of the retina, neovascular condition of the skin, growth-factor-mediated disease, a sclerotic disease, kidney disease, hyper-proliferation of vascular endothelial cells, and hyperplasia.
 52. The method of claim 50, wherein the nucleic acid molecule or modified nucleic acid molecule reduces the level of an IGF, IGF receptor, or IGF-binding protein in the mammal.
 53. The method of claim 50, wherein the nucleic acid molecule or modified nucleic acid molecule is an antisense molecule that reduces the expression of a gene encoding IGF, IGF receptor, or IGF-binding protein. 